Plasmacytoid Dendritic Cells 9811955948, 9789811955945

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Dipyaman Ganguly

Plasmacytoid Dendritic Cells

Plasmacytoid Dendritic Cells

Dipyaman Ganguly

Plasmacytoid Dendritic Cells

Dipyaman Ganguly IICB-Translational Research Unit of Excellence CSIR-Indian Institute of Chemical Biology Kolkata, West Bengal, India

ISBN 978-981-19-5595-2 ISBN 978-981-19-5594-5 https://doi.org/10.1007/978-981-19-5595-2

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© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

Preface

It has been more than 20 years that the plasmacytoid dendritic cells or pDCs were established as a uniquely specialized immune cell and proposed to be a subset of dendritic cells. Dendritic cells are the crucial interlocutors between the innate and adaptive immune system. Accordingly, research over the past almost two decades has revealed the functional dimensions of pDC as an innate-adaptive interlocutor, quite like the conventional dendritic cells (cDCs), but distinct in its functional scopes. There is a necessity for bringing the rich corpus of knowledge in the domain in a single volume, especially for providing a consensus update for a newcomer in the field, a need that was felt by the present author too while being a young graduate student himself. The present work aims to fill that gaping gap, being perhaps the first volume focused solely on scientific understanding about the plasmacytoid dendritic cells and their role in orchestrating the immune response in different pathophysiologic contexts. Research identifying pDCs as the professional type I interferon producers in the body, with plausible affiliation to the dendritic cell lineage, interestingly went in parallel with the research efforts that led to the discovery of cDCs. Ralph Steinman discovered the cDCs in the late 1970s and established the functional phenotypes of these cells over the following one decade along with other groups working in different parts of the world. Possibility of a professional type I IFN producer, in response to infectious agents, also cropped up from experimental data in the late 1970s. The concerted effort by different groups in laboratories all around the world, which finally culminated in identifying pDCs as a distinct dendritic cell subset, was phenomenal in terms of experimental concurrences, incremental insights, and crossvalidations, and it took almost 20 years. The volume begins with the fascinating story of these discoveries, citing the important experiments that provided the individual pieces of the puzzle. This is followed by a brief description of the meticulous developmental studies that traced the hematopoietic development of the two DC subsets, confirming an ontologic basis for the shared lineage affiliation by cDCs and pDCs as well as revealing an intricate transcriptional regulation for the individual cellular identities. v

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Preface

The major functional identity of pDCs, despite their ontogenic affiliation to the DC lineage of professional antigen presenting cells, is the rapid and massive induction of type I IFNs in response to activation of endosomal toll-like receptors (TLRs) by pathogen-derived ligands. First, in a dedicated chapter, we will learn about the specialized mechanisms involved in and pDC-intrinsic molecular regulators of TLR activation. Then we will follow it up with a discussion on the role of pDCs, and type I IFNs released by them, in different contexts of infections, as well as in autoreactive inflammation, as pDCs have been identified over the past decade or so as a crucial player in the pathogenesis of a number of autoimmune diseases as well as chronic inflammation associated with metabolic disorders. Next, a rather anti-inflammatory role, that pDCs are also widely documented to play in varied clinical contexts, viz. allergic immune responses, graft versus host diseases, and cancer, will be discussed. Role of pDCs in driving immune tolerance is identified to be detrimental in such clinical contexts. Finally, we will consider how these diversified roles of pDCs in different contexts of immune response and inflammation necessitate therapeutic targeting of pDCs also to suit the particular contexts as we take stock of varied strategies adopted for targeting pDCs in such discreet clinical contexts. PDCs have been one of the very few immune cell subsets that are both critically involved in the pathogenesis of various human diseases and amenable for therapeutic targeting with already proven efficacies in specific contexts. I hope the present monograph will serve its intended purpose of providing the students and professionals interested in this domain with the necessary basic understanding on this very interesting member of our immune system. A large number of research groups have put efforts in this domain over the past four decades providing with indispensable insights on different aspects of this very important immune cell. The obvious restrictions of space in this volume might have caused a number of such efforts being omitted from the lists of citations. The author seeks sincere apologies for such omissions. I dedicate this volume to all my research mentors, scientific collaborators as well as my mentees, from all of whom I had the opportunity to learn about this extremely interesting immune cell, during my research and academic career in cellular and translational immunology. Kolkata, West Bengal, India

Dipyaman Ganguly

Contents

1

2

3

Discovery of a New Dendritic Cell Subset . . . . . . . . . . . . . . . . . . . . . 1.1 A Brief Biosketch of the Immune System . . . . . . . . . . . . . . . . . . 1.2 Discovery of the Conventional Dendritic Cells . . . . . . . . . . . . . . 1.3 The Search for a Professional Interferon Producer . . . . . . . . . . . . 1.4 A New Dendritic Cell Subset Is the “Professional Interferon Producer” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Origin and Transcriptional Identity of Plasmacytoid Dendritic Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 FLT3-Receptor Dependence and Shared Origin of cDCs and pDCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Myeloid Versus Lymphoid Origin of pDCs . . . . . . . . . . . . . . . . 2.3 Transcriptional Program for pDC Commitment and Function . . . . 2.3.1 E2-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2 IRF8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.3 Regulators of Functional Identity . . . . . . . . . . . . . . . . . . 2.4 Localization and Migration of pDCs . . . . . . . . . . . . . . . . . . . . . 2.5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Activation and Functions of Plasmacytoid Dendritic Cells . . . . . . . . . 3.1 Toll-like Receptor Activation and Signaling in pDCs . . . . . . . . . 3.2 Cell Biology of Endosomal TLR Localization in pDCs . . . . . . . . 3.3 The Cytokine Response in pDCs in Response to TLR Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 Antigen Presentation by pDCs . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5 Cell Biology of Differential pDC Response to TLR Activation . . 3.6 Cellular Metabolism of Activated pDCs . . . . . . . . . . . . . . . . . . . 3.7 The Elusive Role of IL-3 in pDC Immunobiology . . . . . . . . . . . .

1 1 2 4 5 6 8 11 11 12 14 15 16 17 18 19 19 25 25 27 28 32 33 36 38 vii

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Contents

3.8 3.9

Functional Heterogeneity of Plasmacytoid Dendritic Cells . . . . . . Regulators of Type I IFN Induction by pDCs . . . . . . . . . . . . . . . 3.9.1 ILT7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9.2 BDCA2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9.3 Siglec-H . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.10 Other Regulatory Surface Molecules in pDCs . . . . . . . . . . . . . . . 3.11 Endocannabinoids and Cannabinoid Receptors . . . . . . . . . . . . . . 3.12 Metabolite Transporters and Receptors . . . . . . . . . . . . . . . . . . . . 3.13 Effect of Biological Sex on pDC Activation . . . . . . . . . . . . . . . . 3.14 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

39 40 41 41 42 43 45 46 46 47 48

4

Plasmacytoid Dendritic Cells and Infections . . . . . . . . . . . . . . . . . . . 4.1 RNA Viruses and pDCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Human Immunodeficiency Virus and pDCs . . . . . . . . . . . . . . . . 4.3 PDCs and the Novel Coronavirus SARS-CoV-2 . . . . . . . . . . . . . 4.4 DNA Viruses and pDCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5 PDCs in Bacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5.1 Extracellular Bacteria and pDCs . . . . . . . . . . . . . . . . . . . 4.5.2 Intracellular Bacteria and pDCs . . . . . . . . . . . . . . . . . . . . 4.6 PDCs in Malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7 PDCs in Fungal Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

61 61 63 66 66 68 69 70 72 74 75 75

5

Plasmacytoid Dendritic Cells in Autoimmunity . . . . . . . . . . . . . . . . . 5.1 Systemic Lupus Erythematosus . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3 Systemic Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4 Sjogren’s Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5 Role of pDCs in Other Major Rheumatological Disorders . . . . . . 5.6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

85 86 88 92 94 94 97 97

6

Plasmacytoid Dendritic Cells and Metabolic Disorders . . . . . . . . . . . 6.1 Type 1 Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2 Obesity and Type 2 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3 Cardiovascular Components of Metabolic Syndrome . . . . . . . . . . 6.4 Fatty Liver Disease and Hepatic Metaflammation . . . . . . . . . . . . 6.5 A Potential Pathogenic Continuum for Autoimmune Diseases and Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

107 108 108 111 112 113 115 115

Contents

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7

Tolerogenic Functions of Plasmacytoid Dendritic Cells . . . . . . . . . . . 7.1 Thymic pDCs and Central Tolerance . . . . . . . . . . . . . . . . . . . . . 7.2 Mucosal Tolerance Driven by pDCs . . . . . . . . . . . . . . . . . . . . . . 7.3 Tolerogenic pDCs and Tissue Transplantation . . . . . . . . . . . . . . 7.4 Suppression of Anti-cancer Immunity . . . . . . . . . . . . . . . . . . . . . 7.5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

121 122 123 125 127 127 128

8

Plasmacytoid Dendritic Cells and Cancer . . . . . . . . . . . . . . . . . . . . . 8.1 Plasmacytoid Dendritic Cells and the “Cancer-immunity Cycle” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2 Leukemogenesis and pDCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3 Breast Cancer and pDCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.4 Ovarian Carcinoma and pDCs . . . . . . . . . . . . . . . . . . . . . . . . . . 8.5 PDCs in Neoplasmas of the Aero-digestive Tract . . . . . . . . . . . . 8.6 Malignant Melanoma and pDCs . . . . . . . . . . . . . . . . . . . . . . . . . 8.7 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

133

9

Therapeutic Targeting of Plasmacytoid Dendritic Cells . . . . . . . . . . . 9.1 Targeting pDCs and Type I IFNs in Autoreactive Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1.1 Targeting Endosomal TLRs in pDCs . . . . . . . . . . . . . . . . 9.1.2 Biologics Targeting pDCs and Type I IFNs . . . . . . . . . . . 9.2 Targeting pDCs in Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.3 Targeting pDCs in Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.3.1 Targeting Endosomal TLRs and Other pDC-intrinsic Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.3.2 PDC-Based Vaccines for Cancer . . . . . . . . . . . . . . . . . . . 9.4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

133 134 135 137 137 139 140 141 147 147 147 151 151 152 152 154 154 155

Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161

Chapter 1

Discovery of a New Dendritic Cell Subset

1.1

A Brief Biosketch of the Immune System

The immune system in the body of the higher animals, if not in all multicellular organisms, provides for a specialized division of labor, to a cell or to groups of cells that, (a) perform sentinel function to look for potential pathogens invading the body (in the context of infections) or transformed self-origin cells (in the context of cancers), and (b) try to neutralize the plausible “danger” posed by such occurrences to the anatomic and physiological integrity of the body. Phylogeny has diversified the cellular participants in this critical bodily function to two distinctive axes of innate immunity and adaptive immunity in higher animals. The innate immune cells (e.g., neutrophils, macrophages, natural killer or NK cells) perform the sentinel function as well as take up reflexive mitigating missions through release of biochemical mediators or otherwise. The adaptive immune cells (viz. T and B lymphocytes) expressing editable antigen receptors on their cell surface, educate themselves with the molecular identity of the “danger,” be it pathogens or transformed self-origin cells, and prepare for more efficient assault on future encounters, by either working on their antigen receptors (e.g., the B cell receptor or BCR) or selecting and expanding cellular clones expressing the most relevant and efficient antigen receptors (e.g., in case of T cells expressing specific T cell receptors or TCRs) or both. The decision taken by innate immune cells to get activated and initiate immune response depends on a range of cell surface and cytosolic receptors expressed by them, named the pattern recognition receptors or PRRs (viz. Toll-like receptors or TLRs, RIG-I like receptors or RLRs, NOD-like receptors or NLRs, C-type lectin receptors or CLRs). These receptors are neither selectable nor editable, unlike the TCRs or BCRs, respectively, recognize molecular patterns that are of either pathogenic origin (the pathogen associated molecular patterns or PAMPs, e.g. bacterial lipopolysaccharides, lipoproteins, flagellin, viral nucleic acids, etc.) or are known to signal various intracorporeal “danger” (the danger associated molecular patterns or © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 D. Ganguly, Plasmacytoid Dendritic Cells, https://doi.org/10.1007/978-981-19-5595-2_1

1

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Discovery of a New Dendritic Cell Subset

DAMPs, e.g. uric acid crystals, extracellular nucleic acids, nucleic acid binding proteins like HMGB1 or LL-37, heat shock proteins). Recognition of such PAMPs or DAMPs by the PRRs on the innate immune cells serves to activate them in relevant contexts and initiate immune response. The biochemical mediators released by the innate immune cells on one hand tries to neutralize the offending entities they encounter, and on the other hand alerts the adaptive immune system by inviting adaptive immune cells to the scene of perceived offense and by promoting their activation. As the “danger”-mitigating mediators are mostly soluble biochemicals (e.g., various cytokines and chemokines), along with more limited mechanisms of cellular contact-based cytotoxicity—a major fall-out of an overzealous immune response is undesirable host tissue damage. Thus mechanisms need to be incorporated within the immunocellular repertoire that can prevent such “horror autotoxicus,” as was the apprehension of Paul Ehrlich on discovering some of the soluble mediators of immunity. Indeed, both in terms of specialized cellular commitments and property of certain cytokines, a sizeable number of the so-called tolerance mechanisms also operate within the immune system. All peripheral immune cells are hematopoietic in origin, develop in the bone marrow, and are released into the circulation. For T cells a brief detour to the thymus happens wherein predominantly non-self-reactive T cell clones are “selected” and released into the circulation. The immune cells circulate throughout the body, with some cells finding longer residence in tissue spaces (a number of innate immune cells like macrophages), some in the secondary lymphoid organs, e.g. lymph nodes (most of the T cells and B cells). The operational algorithm of an immune response that is apparent from this brief biosketch lacks a major piece of the jigsaw puzzle. The education of the adaptive immune cells happens in the secondary lymphoid organs, while the first encounter with the relevant antigens is bound to happen mostly in the peripheral tissues. Thus a cellular commitment toward transfer of antigens from the tissues to the lymph nodes and cellular crosstalk between such migratory cells with the adaptive immune cells (the so-called antigen presentation), that preferably should happen in the lymph nodes, are essential for the adaptive education. Discovery of the immune cells called dendritic cells in the 1970s provided with this piece of the puzzle.

1.2

Discovery of the Conventional Dendritic Cells

A major experimental help, for identifying such a specialized cell that can engage with adaptive immune cells like T cells and educate them, was provided by an in vitro immune cell culture system developed in Scripps Research Institute in La Jolla (Mishell and Dutton 1967). This experiment, which involved mixing antigens with lymphocytes in vitro and measuring antibody production, revealed that apart from the lymphocytes some as of then unidentified accessory cell was necessary for the experiment to work. The only information about the cells that were available then was their property of adherence to glass and presentation of antigen to the

1.2

Discovery of the Conventional Dendritic Cells

3

lymphocytes. In early 1970s Ralph Steinman, alongside Zanvil A. Cohn in Rockefeller University in New York City, tried to identify and purify these accessory cells for further studies. The usual idea of immunologists around that time attributed the accessory cell function to macrophages, which are more abundant and have efficient phagocytic activity, and cells looking like them had been shown to be around labeled antigens in vivo in the lymph nodes in a study done in Walter and Eliza Hall Institute in Melbourne (Nossal et al. 1968). Nevertheless, Cohn and Steinman in their experiments found that antigens loaded into purified macrophages were efficiently degraded intracellularly with no trace of them on the cell surface, which was presumed to be essential for antigen presentation to lymphocytes (Ehrenreich and Cohn 1967; Steinman and Cohn 1972). The 1974 Nobel Prize in Physiology or Medicine went to George Palade, for devising methods for fixation and electron microscopy of cells, and Christian de Duve, who developed centrifugation methods to isolate subcellular components. Both of them worked in Rockefeller University, and Steinman and Cohn utilized both these newly devised cell biological techniques to identify the accessory cells from mouse lymphoid organs, especially spleen. Single cell suspension of spleen cells were put to de Duve’s density gradient centrifugation method using bovine serum albumin, to separate the accessory cell fraction from the lymphocytes, as the former went to the top and the latter went to the bottom due to their physical properties. Further purification using the previously reported glass-adherence property perhaps enriched a cellular fraction containing macrophages as well as the unidentified accessory cells. Finally, on removing macrophages by characteristic rosetting using red blood cells, the pure accessory cells were isolated. The cells showed a characteristic “dendritic” morphology showing tree-like cellular extensions under light microscopy as well as electron microscopy (the word comes from the Greek word “dendreon” meaning tree), with very little phagocytic vacuoles, quite unlike macrophages (Steinman and Cohn 1973). Soon it was demonstrated that in mixed lymphocyte reactions wherein purified dendritic cells from one mouse strain were put in culture with T cells from another strain, dendritic cells were hundred-fold more potent in inducing the T cell proliferation as compared to unfractionated splenocytes, despite being very rare in frequency (Steinman and Witmer 1978; Inaba et al. 1983; Inaba and Steinman 1985). These data were supported by depletion experiments as well, due to the development of a monoclonal antibody specific for these dendritic fraction of the splenocytes (Nussenzweig et al. 1982). Availability of antibodies also helped to identify localization of DCs in the body, showing their presence almost at all interfaces with the environment, viz. skin and mucosal surfaces, as well as in the secondary lymphoid organs, viz. spleen, lymph nodes, tonsils, and thymus, supporting their putative sentinel functions as well as antigen presentation in these lymphoid organs. Since its first description over the last 50 years or so, the dendritic cell family of immune cells (DCs) has been established to be a critical cellular member of the immune system in humans, if not in all vertebrates, which lies neither exclusively in the innate immune arm nor in the adaptive immune arm. DCs rather connect the two axes, by performing sentinel functions in the tissue spaces by sampling antigens and,

4

1

Discovery of a New Dendritic Cell Subset

followed by migration to the lymph nodes, presenting the antigens to the antigeninexperienced T cells and priming them for activation (or tolerance). The classical description of DCs arrived at over the years has been their surface expression of characteristic protein markers, viz. CD11c, DC-SIGN, etc., the so-called dendritic cell markers. They are also characterized by their steady state high expression of MHC class II molecules (HLA-DR in humans), which enable them to efficiently present both exogenous and endogenous (cross-presentation) antigens to CD4 T cells, apart from MHC class I molecules which are more ubiquitous and help them to present endogenous antigens to CD8 T cells. And, finally the characteristic DC maturation program is also established, which they undergo in response to acquisition of antigens and PRR activation, leading to migration to the lymph nodes and expression of a set of costimulatory molecules (viz. CD83, CD80, and CD86) etc. which are employed in efficient priming of the T cells (Steinman 2012). On one hand, the family expanded as DCs in different parts of the bodies could be distinguished based on characteristic surface protein expression, functional commitments as well as transcriptional programs based on recent single RNA sequencing efforts (Eisenbarth 2019; Ginhoux et al. 2022). On the other hand, the mechanisms of PRR activation and its effect on functional changes on DCs as well as the intricate details of intracellular antigen processing pathways have also been established through studies done all over the world (Akira and Takeda 2004; Pishesha et al. 2022). Ralph Steinman received the Nobel Prize in Medicine and Physiology in 2011 for discovering dendritic cells, actually the classically described dendritic cells, which will refer to hereafter as the conventional DCs or cDCs.

1.3

The Search for a Professional Interferon Producer

Since the 1930s scientists who worked with viruses and explored how viruses infect the host cells encountered an enigmatic phenomenon. It was time and again found that one virus can block infection of host cells with another virus if they are put in the same culture or even in the same animal (Isaacs and Burke 1959). Even inactivated influenza virus was shown to inhibit infection of host cells by live influenza viruses (Henle and Henle 1943). This phenomenon was called “virus interference” and it was not until 1957 that Alick Isaacs and Jean Lindenmann, in National Institute of Medical Research in London, published their seminal experiments to show that a soluble factor, not of viral origin, but produced by the host cells was responsible for the phenomenon (Isaacs and Lindenmann 1957; Isaacs et al. 1957). In the original paper itself they named the soluble mediator as “interferon.” The story we are interested in starts with experiments done in late 1970s by Georgio Trinchieri’s group in Wistar Institute in Philadelphia, wherein co-culture of human peripheral blood mononuclear cells with virus-infected cells showed copious production of interferons, especially interferon-α (IFN-α), which in turn had the same interference or antiviral activity (Trinchieri et al. 1978). Gunnar Alm’s group in University of Uppsala demonstrated in 1983 that not only viruses, but also bacteria, both killed or live, could induce production of IFN-α (Rönnblom et al.

1.4

A New Dendritic Cell Subset Is the “Professional Interferon Producer”

5

1983a). Thus a search began for a circulating immune cell that had the ability to produce interferon in response to viruses, or a “professional interferon producer” among the immune cells. Alm’s group also tried to fractionate the IFN-producing cells from their culture to identify it and reported these IFN-producers not to be T cell, B cell or NK cells and to be plastic non-adherent (Rönnblom et al. 1983b). They designated the cells as the “natural interferon producing cells” (NIPCs) in the human body, due to their immense ability to rapidly produce hundred-fold more interferons as opposed to other cells in response to viruses.

1.4

A New Dendritic Cell Subset Is the “Professional Interferon Producer”

A seminal study done in Trinchieri’s lab, published in 1985, aimed at characterizing this plastic-non-adherent human peripheral blood mononuclear cell responsible for IFN-α production in response to several different viruses (viz. influenza, Sendai, and Newcastle disease virus) by meticulous depletion and recovery of specific immune cells using a plethora of monoclonal antibodies specific for different immune cell subsets. This study first reported that these NIPCs in human PBMCs, present in very low frequency (1–1.5% in their estimate), did not express any characteristic surface markers of lymphocytes or myeloid cells, and expressed the human MHC class II molecule HLA-DR in the steady state (Perussia et al. 1985). They also confirmed the non-NK cell identity of the cell by demonstrating absence of HLA-DR on NK cells and inability of the HLA-DR+ NIPCs to mediate cytotoxicity to tumor cells. Perhaps this report first suggested that these so-called NIPCs can be related to dendritic cells, as they are similarly HLA-DR+. This finding was further supported by Stuart Starr’s group in Wistar Institute in a study which reported that these HLA-DR+ NIPCs were essential to enable NK cells to kill cytomegalovirus-infected fibroblasts (Bandyopadhyay et al. 1986). The non-NK cell identity and HLA-DR positivity of NIPCs were also independently confirmed by Patricia Fitzgerald-Bocarsly’s group in New Jersey Medical School in Newark (Fitzgerald-Bocarsly et al. 1988). Follow-up studies by Fitzerald-Bocarsly’s group and Charles Rinaldo’s group in University of Pittsburgh did not distinguish between the NIPC and the cDCs and attributed the function to dendritic cells circulating in the blood (Feldman and Fitzgerald-Bocarsly 1990; Ferbas et al. 1994). However, Santu Bandyopadhyay’s group at Joseph Stokes Institute in Philadelphia already had confirmed that these HLA-DR+ NIPCs were distinct from the conventional DCs, as in contrast to cDCs the NIPCs were much less efficient to drive lymphocyte proliferation in mixed lymphocyte reactions, pointing to their relative inefficiency as antigen presenting cells (Chehimi et al. 1989). In completely disconnected effort of scientific pursuit in clinical pathology, Karl Lennert and Wolfgang Remmele at Goethe University in Frankfurt identified cells with morphological similarity with plasma cells in the T cell areas of lymph nodes

6

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Discovery of a New Dendritic Cell Subset

and spleen in human (Lennert and Remmele 1958). Subsequently cells with similar morphology were reported by histopathology studies in Hodgkin’s lymphoma as well as other disease involving lymph nodes including Castleman’s disease and were variably designated as plasmacytoid lymphocytes, plasmacytoid T cells or even plasmacytoid monocytes, based mostly on their morphology as described by Lennert and their location in the T cell area of the lymph nodes (Henry 1975; Paulutke et al. 1976; Facchetti et al. 1988). A major clue for the similarity of identity between the plasmacytoid monocytes or plasmacytoid T cells came when Yong-Jun Liu’s group in Schering-Plough Laboratory in Dardilly isolated these cells from the T cell regions of human tonsils and showed their dependence on interleukin-3 (IL-3) for survival and activation by CD40 ligand (Grouard et al. 1997). On electron microscopy on the purified cells a characteristically extensive endoplasmic reticulum and golgi network was demonstrated, conforming to the “plasmacytoid” description given by the histopathology studies. The cells were designated to be type 2 dendritic cells or DC2 cells as on being cultured with IL-3 and CD40 ligand the activated cells were able drive type 2 helper cell polarization. Soon Marco Colonna’s group in Basel Institute of Immunology isolated them from human blood and showed that they produce large amounts of IFN-α in inflamed lymph nodes, followed by Liu’s group confirming this identity of professional interferon producers (Cella et al. 1999; Siegal et al. 1999). Thus a new dendritic cell subset, which expressed HLA-DR, was less efficient than conventional DCs in terms of antigen presentation, much more efficient than any other cell in rapidly producing large amounts of IFN-α in response to viruses, and presumably for this characteristic protein synthetic and secretory function had a plasma cell-like intricate ER-golgi network, giving it the plasmacytoid morphology, was finally described (Fig. 1.1). Soon, the natural interferon producing cells were widely started being designated as plasmacytoid dendritic cells (Colonna et al. 2004).

1.5

Conclusion

The history of discovery of both the DC subsets, more so in case of plasmacytoid DCs, put forward a vivid story of how intriguing observations and meticulous experimentations by different research groups working separately can achieve breakthroughs in science. Since its final definitive description and independent designation, back in 1999, the pDCs have intrigued generations of scientists all over the world which enabled us to appreciate the developmental path and the regulatory mechanisms of this unique immune cell subset as well as the crucial role this cell plays in different patho-physiologic contexts. Apart from the major diversification of the dendritic cell lineage into cDCs and pDCs, the cDC lineage have further been documented to comprise of distinct tissuespecific and functionally specialized subsets, which can also be distinguished by their expression of characteristic receptors on the cell surface (Fig. 1.2). The major

1.5

Conclusion

7

Fig. 1.1 Characteristic morphology of plasmacytoid dendritic cells. (a) Transmission electron micrograph human plasmacytoid dendritic cells showing the characteristically extensive endoplasmic reticulum and Golgi network, devoid of dencritic processes unlike conventional dendritic cells. (Reused with permission from Collin M et al., 2011). (b) Scanning electron micrograph of human plasmacytoid dendritic cells

differentiated subsets among the circulating cDCs are the BDCA1+ (or CD1c+ as shown in Fig. 1.2) cDCs and the BDCA3+ (or CD141+ as shown in Fig. 1.2) cDCs. Moreover, circulating monocytes have been shown to assume cDC phenotype in inflammatory contexts in vivo as well as in vitro. The immunobiology of the conventional DCs has been covered in great detail in other volumes and excellent reviews elsewhere and it is not within the scope of this volume (Lombardi and RiffoVasquez 2009; Collin et al. 2011; Anderson et al. 2021; Ginhoux et al. 2022). Further diversification among pDCs are not yet established in terms of functional specialization or distinct transcriptional identity. Nevertheless, a few instances of suggested functional specializations among pDCs will be discussed later, as we explore the extensive knowledge that have been gathered since the discovery of the plasmacytoid dendritic cells about their ontogenic development (confirming their affiliation to the dendritic cell lineage), molecular regulation of the cellular identity, major functional attributes and the key role they play in orchestrating the immune response in different patho-physiological contexts.

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Discovery of a New Dendritic Cell Subset

Fig. 1.2 Major subsets of human and mouse dendritic cells. The characteristic surface receptor expression profiles and functional attributes of major subsets of conventional dendritic cells and plasmacytoid dendritic cells, both in human and in mouse, have been shown. (Reproduced with permission from Collin M et al., 2011)

References Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4(7):499–511. https:// doi.org/10.1038/nri1391 Anderson DA 3rd, Dutertre CA, Ginhoux F, Murphy KM (2021) Genetic models of human and mouse dendritic cell development and function. Nat Rev Immunol 21(2):101–115. https://doi. org/10.1038/s41577-020-00413-x Bandyopadhyay S, Perussia B, Trinchieri G, Miller DS, Starr SE (1986) Requirement for HLA-DR + accessory cells in natural killing of cytomegalovirus-infected fibroblasts. J Exp Med 164(1): 180–195. https://doi.org/10.1084/jem.164.1.180 Cella M, Jarrossay D, Facchetti F, Alebardi O, Nakajima H, Lanzavecchia A, Colonna M (1999) Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat Med 5(8):919–923. https://doi.org/10.1038/11360

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Chehimi J, Starr SE, Kawashima H, Miller DS, Trinchieri G, Perussia B, Bandyopadhyay S (1989) Dendritic cells and IFN-a producing cells are two functionally distinct non-B, non-monocytic HLA-DR+ cell subsets in human peripheral blood. Immunology 68(4):486–490 Collin M, Bigley V, Haniffa M, Hambleton S (2011) Human dendritic cell deficiency: the missing ID? Nat Rev Immunol 11(9):575–583. https://doi.org/10.1038/nri3046 Colonna M, Trinchieri G, Liu YJ (2004) Plasmacytoid dendritic cells in immunity. Nat Immunol 5(12):1219–1226. https://doi.org/10.1038/ni1141 Ehrenreich BA, Cohn ZA (1967) The uptake and digestion of iodinated human serum albumin by macrophages in vitro. J Exp Med 126(5):941–958. https://doi.org/10.1084/jem.126.5.941 Eisenbarth SC (2019) Dendritic cell subsets in T cell programming: location dictates function. Nat Rev Immunol 19(2):89–103. https://doi.org/10.1038/s41577-018-0088-1 Facchetti F, Wolf-Peeters C, Mason D, Pulford K, Van den Oord J, Desmet V (1988) Plasmacytoid T cells. Immunohistochemical evidence for their monocyte/macrophage origin. Am J Pathol 133(1):15–21 Feldman M, Fitzgerald-Bocarsly P (1990) Sequential enrichment and immunocytochemical visualization of human interferon-a producing cells. J Interf Res 10:435–446 Ferbas JJ, Toso JF, Logar AJ, Navratil JS, Rinaldo CR (1994) CD4+ blood dendritic cells are potent producers of IFN-a in response to in vitro HIV-1 infection. J Immunol 152:4649–4662 Fitzgerald-Bocarsly P, Feldman M, Mendelsohn M, Curl S, Lopez C (1988) Human mononuclear cells which produce interferon-alpha during NK (HSV-FS) assays are HLA-DR positive cells distinct from cytolytic natural killer effectors. J Leukoc Biol 43:323–334 Ginhoux F, Guilliams M, Merad M (2022) Expanding dendritic cell nomenclature in the single-cell era. Nat Rev Immunol 22(2):67–68. https://doi.org/10.1038/s41577-022-00675-7 Grouard G, Rissoan M, Filguiera L, Durand I, Banchereau J, Liu YJ (1997) The enigmatic plasmacytoid T cells develop into dendritic cells with interleukin-3 and CD40 ligand. J Exp Med 185(6):1101–1111. https://doi.org/10.1084/jem.185.6.1101 Henle W, Henle G (1943) Interference of inactive virus with the propagation of virus of influenza. Science 98(2534):87–89. https://doi.org/10.1126/science.98.2534.87 Henry K (1975) Electron microscopy in the non-Hodgkin’s lymphomata. Br J Cancer Suppl 2:73– 93 Inaba K, Steinman RM (1985) Protein-specific helper T-lymphocyte formation initiated by dendritic cells. Science 229(4712):475–479. https://doi.org/10.1126/science.3160115 Inaba K, Granelli-Piperno A, Steinman RM (1983) Dendritic cells induce T lymphocytes to release B cell-stimulating factors by an interleukin 2-dependent mechanism. J Exp Med 158(6): 2040–2057. https://doi.org/10.1084/jem.158.6.2040 Isaacs A, Burke DC (1959) Viral interference and interferon. Br Med Bull 15:185–188. https://doi. org/10.1093/oxfordjournals.bmb.a069760 Isaacs A, Lindenmann J (1957) Virus interference. 1. The interferon. Proc R Soc Lond B Biol Sci 147:258–267 Isaacs A, Lindemann J, Valentine RC (1957) Virus interference. II. Some properties of interferon. Proc R Soc Lond B Biol Sci 147(927):268–273. https://doi.org/10.1098/rspb.1957.0049 Lennert K, Remmele W (1958) Karyometric research on lymph node cells in man. I. Germinoblasts, lymphoblasts & lymphocytes. Acta Haematol 19(2):99–113. https://doi.org/10.1159/ 000205419 Lombardi G, Riffo-Vasquez Y (eds) (2009) Dendritic cells. Springer, Berlin. https://doi.org/10. 1007/978-3-540-71029-5 Mishell RI, Dutton RW (1967) Immunization of dissociated spleen cell cultures from normal mice. J Exp Med 126(3):423–442. https://doi.org/10.1084/jem.126.3.423 Nossal GJ, Abbot A, Mitchell J, Lummus Z (1968) Antigens in immunity. XV. Ultrastructural features of antigen capture in primary and secondary lymphoid follicles. J Exp Med 127(2): 277–290. https://doi.org/10.1084/jem.127.2.277

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Nussenzweig MC, Steinman RM, Witmer MD, Gutchinov B (1982) A monoclonal antibody specific for mouse dendritic cells. Proc Natl Acad Sci U S A 79(1):161–165. https://doi.org/ 10.1073/pnas.79.1.161 Paulutke M, Khilanani P, Weise R (1976) Immunologic and electronmicroscopic characteristics of a case of immunoblastic lymphadenopathy. Am J Clin Pathol 65(6):929–941. https://doi.org/10. 1093/ajcp/65.6.929 Perussia B, Fanning V, Trinchieri G (1985) A leukocyte subset bearing HLA-DR antigens is responsible for in vitro alpha interferon production in response to viruses. Nat Immun Cell Growth Regul 4:120–137 Pishesha N, Harmand TJ, Ploegh HL (2022) A guide to antigen processing and presentation. Nat Rev Immunol. https://doi.org/10.1038/s41577-022-00707-2 Rönnblom L, Forsgren A, Alm GV (1983a) Characterization of interferons induced by bacteria and interferon-producing leukocytes in human peripheral blood. Infect Immun 40(1):126–132. https://doi.org/10.1128/iai.40.1.126-132.1983 Rönnblom L, Ramstedt U, Alm GV (1983b) Properties of human natural interferon-producing cells stimulated by tumor cell lines. Eur J Immunol 13:471–476 Siegal F, Kadowaki N, Shodell M, Fitzgerald-Bocarsly PA, Shah K, Ho S, Antonenko S, Liu YJ (1999) The nature of the principal type 1 interferon-producing cells in human blood. Science 284(5421):1835–1837. https://doi.org/10.1126/science.284.5421.1835 Steinman RM (2012) Decisions about dendritic cells: past, present, and future. Annu Rev Immunol 30:1–22. https://doi.org/10.1146/annurev-immunol-100311-102839 Steinman RM, Cohn ZA (1972) The interaction of particulate horseradish peroxidase (HRP)-anti HRP immune complexes with mouse peritoneal macrophages in vitro. J Cell Biol 55(3): 616–634. https://doi.org/10.1083/jcb.55.3.616 Steinman RM, Cohn ZA (1973) Identification of a novel cell type in peripheral lymphoid organs of mice. I. morphology, quantitation, tissue distribution. J Exp Med 137(5):1142–1162. https://doi. org/10.1084/jem.137.5.1142 Steinman RM, Witmer MD (1978) Lymphoid dendritic cells are potent stimulators of the primary mixed leukocyte reaction in mice. Proc Natl Acad Sci U S A 75(10):5132–5136. https://doi.org/ 10.1073/pnas.75.10.5132 Trinchieri G, Santoli D, Dee RR, Knowles BB (1978) Anti-viral activity induced by culturing lymphocytes with tumor derived or virus-transformed cells. Identification of the anti-viral activity as interferon and characterization of the human effector lymphocyte subpopulation. J Exp Med 147:1299–1313

Chapter 2

Origin and Transcriptional Identity of Plasmacytoid Dendritic Cells

Plasmacytoid dendritic cells (pDCs) are released into peripheral circulation as mature cells, present in very low frequency (0.1–0.5% of cells in mouse) from the bone marrow. In the bone marrow they are generated incessantly by proliferation and differentiation of the progenitor cells and thus pDC frequency in the bone marrow is much higher at 1–2% (as found in mice). On the other hand in the periphery, both in circulation and in lymphoid organs, they hardly, if at all, proliferate. PDCs have quite a short lifespan as shown by BrdU labeling experiments in vivo in mice, very similar to conventional DCs (cDCs), which can be up to just 3–6 days (Zhan et al. 2016). In this chapter we learn about the current understanding on the hematopoietic origin of pDCs and the transcriptional program necessary for achieving and maintaining the pDC identity.

2.1

FLT3-Receptor Dependence and Shared Origin of cDCs and pDCs

A major characteristic of all DC subsets, both cDCs and pDCs, is the expression of CD135 or Fms-like tyrosine kinase 3 (FLT3), the receptor for the cytokine FLT3 ligand or FLT3L (D’Amico and Wu 2003; Karsunky et al. 2003). FLT3 is a receptor tyrosine kinase that bears homology with kinases c-Kit and c-Fms (Lyman and Jacobsen 1998). Mouse bone marrow cells cultured in vitro in the presence of FLT3L give rise to cDCs and pDCs in large numbers, but very few of other cells (Gilliet et al. 2002). In humans too, overexpression of FLT3 in FLT3+ hematopoietic progenitors drive enhanced differentiation of cDCs and pDCs and the same in FLT3- progenitors rescues their potential to generate DCs (Onai et al. 2006). It has also been shown that FLT3 is critically needed for regulation of homeostatic DC differentiation in the spleen, from the bone marrow-derived immature DCs to mature DCs (Waskow et al. 2008). © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 D. Ganguly, Plasmacytoid Dendritic Cells, https://doi.org/10.1007/978-981-19-5595-2_2

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Origin and Transcriptional Identity of Plasmacytoid Dendritic Cells

The fact that addition of FLT3L in bone marrow cell cultures give rise to both cDCs and pDCs led to the suggestion that these two DC subsets may share a committed DC progenitor, downstream of the myeloid progenitors. In a seminal study, by focusing on the putative cytokines that are expected to drive DC differentiation a lineage- FLT3+ CSF1R+ population (that should respond to FLT3L as well as M-CSF, the myeloid colony stimulating factor which uses CSF1R as it receptor) was first purified from the mouse bone marrow cells with the potential to differentiate into both cDCs and pDCs, but nothing else (Onai et al. 2007). In a parallel study the shared DC progenitor cells was identified as low-density dividing cells among the FLT3L cultured bone marrow cells at day 3 which were negative for MHC class II molecules and the lymphoid progenitor marker IL-7 receptor (Naik et al. 2007). DC differentiation potential for these cells were evaluated in vivo by transferring into recipient mice and enumerating splenic DCs from the transferred cells, as well as in fresh FLT3L cultures. Thus a common DC progenitor cell (CDP) was discovered and the sharing of proximal cellular origin for cDCs and pDCs was established, formally justifying DC affiliation for pDCs. CDPs identified in both these studies were FLT3+ CSF1R+ cells. Apart from FLT3L, a role of M-CSF in pDC differentiation was also soon described (Fancke et al. 2008). Soon it was found that upstream of CDP lies another progenitor subset that has potential for generating both macrophages and DCs (both cDCs and pDCs), thus called the macrophage-DC progenitor cells (MDPs). This established a major, if not exclusive, myeloid lineage origin for pDCs (Auffray et al. 2009; Liu et al. 2009). A more committed progenitor for pDCs, downstream of CDPs were also soon identified by two groups, one identifying it as CSF1R- cells downstream of CDPs, the other as CCR9- cells with low expression of MHC class II molecules (Onai et al. 2013; Schlitzer et al. 2011). Interestingly, The CSF1R- cells were suggested to have potential origin from both myeloid (downstream of MDPs and CDPs) and lymphoid lineages (Onai et al. 2013). In another study, using clonal culture and adoptive transfer to track DC differentiation in mice, it was found that the MDPs, as described by earlier studies, hardly contain bi-potent precursor cells (with potential for generating both macrophage/monocytes and DCs) – the major yield from these cells were found by this study to be macrophages and monocytes (Sathe et al. 2014). Thus existence of a bi-potent macrophage-DC precursor or the so-called MDPs remains debatable (Onai and Ohteki 2014).

2.2

Myeloid Versus Lymphoid Origin of pDCs

The hematopoietic origin of pDCs has often been indicated, even in early studies, to be of multiple hematopoietic progenitor cells, as they can be generated from both myeloid and lymphoid progenitors in experiments (D’Amico and Wu 2003; Karsunky et al. 2003). Another reason for the suggestion of at least a partial lymphoid origin of pDCs perhaps stems from the fact that a lot of genes involved in early lymphoid development, viz. Dntt, VpreB, PTCRA, and Rag1/2, are

2.2

Myeloid Versus Lymphoid Origin of pDCs

13

expressed in pDCs (Corcoran et al. 2003; Shigematsu et al. 2004; Harman et al. 2006). Interestingly, their expression varies among pDCs in different species, e.g. PTCRA is expressed on only human pDCs, but not in mice. Moreover, expression of such genes are not restricted to pDCs with lymphoid origin, as pDCs generated from either lymphoid or myeloid progenitors can express such genes (Shigematsu et al. 2004). Thus expression of these genes may not solely be linked to their developmental origin (Reizis 2010). Interestingly, when lineage- c-kit+ sca-1- CD16/32low CD34+ common myeloid progenitor cells (CMPs) and lineage- CD127+ c-kitint sca-1+ common lymphoid progenitor cells (CLPs) were purified from mouse bone marrow and cultured only in presence of FLT3L, CMPs were found to produce both cDCs and pDCs with a peak of pDC abundance in culture around day 7, while CLPs differentiated into pDC, but not cDCs, with a peak around day 5 (Sathe et al. 2013). This data further supported earlier studies reporting potential of both myeloid and lymphoid progenitors to produce pDCs in vivo (Shigematsu et al. 2004). More recently a significant effort has been put into characterizing the identity of lymphoid progenitors of pDCs in several studies. In one study CSF1R- IL7R+ lymphoid progenitors, which are established to be the major progenitors for B cells, were found to generate more Siglec-H+ CD317+ pDCs compared to the CSF1R+ IL7R- CDPs (Rodrigues et al. 2018). These pDC-committed CSF1R- IL7R+ lymphoid progenitors are present in a very low frequency in bone marrow, estimated to be approximately 0.12% of total bone marrow cells and approximately 0.04% of the Sca1+ CLPs (Kondo et al. 1997; Rodrigues et al. 2018). It was further reported that within this lymphoid progenitors a Siglec-H+ Ly6D+ subset had the potential for developing into pDCs instead of B cells. Another study by performing single-cell RNA sequencing on hematopoietic progenitors, with subsequent specialized cluster and lineage tracing analysis based on the transcriptional signature, also proposed a shared precursor for B cells and pDCs expressing IL7R, which could be further subdivided into a Rag1hi subset with B cell differentiation potential and a Rag1lo subset differentiating into pDCs (Herman et al. 2018). Nevertheless, it is also suggested that the usually very low frequency of the pDC-committed lymphoid progenitors is incommensurate with these being the most important precursors for pDCs, which are considerably abundant, for example, in bone marrow cultures in presence of FLT3L. Notably, Herman et al. also identified a precursor for pDCs in the myeloid lineage and transcriptional vicinity for cDCs and pDCs. This was also reported in a study which generated transgenic mice that express yellow fluorescence protein (YFP) under the control of CSF1R promoter. This led to YFP expression in all myeloid cells and cDCs, as well as in a major fraction of pDCs, thus confirming a major myeloid (i.e., CDP) contribution to pDC lineage (Loschko et al. 2016). In a more recent study, using an intricate inducible lineage tracing using clonal DNA barcoding combined with single-cell transcriptome of hematopoietic stem cells and Cx3Cr1+ progenitor cells, an absence of lineage sharing between pDCs and B cells and shared origin of pDCs and the cDC1 subsets were reported (Feng et al. 2022). Thus the current consensus in the field is that majority of pDCs (documented mostly in mice, and reasonably expected to be similar in humans) develop from the CDPs

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Origin and Transcriptional Identity of Plasmacytoid Dendritic Cells

Fig. 2.1 Hematopoietic development of major immune cells including dendritic cell subsets. Diversification of immunocellular lineages as they develop from the hematopoietic stem cells passing through different progenitor states with gradual fixation of lineage affiliations is shown. The major transcriptional regulators are also depicted for each cellular state (described in detail in Anderson et al. 2021)

sharing their myeloid origins with cDCs, with a minor additional contribution from a lymphoid progenitor shared with B cells (Reizis 2019; Anderson et al. 2021). Figure 2.1 depicts the current consensus knowledge on the hematopoietic developmental pathway for dendritic cells, among all other immune cells.

2.3

Transcriptional Program for pDC Commitment and Function

As we discussed earlier, FLT3L by itself is essential and sufficient for pDC development from the progenitor cells. Thus it is expected that there exists a robust pDC-specific transcriptional program capable of driving progenitors to commit to pDC fate at the expense of a cDC commitment. The ETS family transcription factor PU.1 regulates a number of genes in both the myeloid and lymphoid lineage cells, most importantly genes for the cytokine receptors critical for development of different hematopoietic cells, viz. CSF1R, IL7R and receptor for granulocytemacrophage colony stimulating factor (GM-CSFR). It is also established that the FLT3L-driven DC development through CDP (for both cDCs and pDCs) is critically

2.3

Transcriptional Program for pDC Commitment and Function

15

Fig. 2.2 Transcriptional regulators of plasmacytoid dendritic cell identity. Major transcription factors downstream of key growth factor signaling and their cross-regulation, which define the developmental commitment and maintenance of cellular identity for plasmacytoid dendritic cells are shown. (Image by Dipyaman Ganguly 2022)

dependent on PU.1, as conditional deficiency of Sfpi1 (the gene encoding PU.1) blocks DC development both in vitro and in vivo. Haplodeficiency of Sfpi1 also leads to reduced expression of FLT3 receptor (Carotta et al. 2010). Figure 2.2 depicts the major transcriptional regulators of pDC identity and their cross-regulations.

2.3.1

E2-2

The question of which transcriptional specialization drives the diversification of pDCs downstream of CDP and away from the cDC affiliation was answered by studies that reported the basic helix-loop-helix transcription factor E2-2 (or Tcf4) to be enriched in expression in both murine and human pDCs (Cisse et al. 2008; Nagasawa et al. 2008). When in mouse E2-2 was either constitutively or inducibly deleted development of pDCs was blocked, while it did not affect any other immune cell lineage (Cisse et al. 2008). Lack of E2-2 also abrogated type I IFN induction in pDCs in response to TLR9 activation. E2-2 is haplo-insufficient. Haplodeficiency in mouse was associated with impaired type I IFN response in mouse pDCs as well as in human pDCs from patients with the related genetic disorder Pitt-Hopkins Syndrome (Cisse et al. 2008). Moreover, sustained expression of E2-2 is essential for pDCs to maintain the phenotype. Deletion of E2-2 even in mature pDCs causes spontaneous differentiation into cells with cDC-like phenotypes, viz. loss of pDC markers, increased in MHC-II expression, increased antigen presentation to T cells, a

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Origin and Transcriptional Identity of Plasmacytoid Dendritic Cells

dendritic cellular morphology, and expression of genes characteristic of cDCs (Ghosh et al. 2010). Function of E2-2 is further supported by other cofactors, e.g. MTG16 and BCL11A, as demonstrated in mice. Although BCL11A regulate both IL7R and FLT3 expression in the progenitors, BCL11-deficient mice were found to be deficient in specifically pDCs and it was found that BCL11A also regulates the expression of critical regulators of DC development and differentiation, e.g. E2-2, MTG16, and ID2 in mice (Wu et al. 2013; Ippolito et al. 2014). While pDC development is driven by E2-2, the E protein antagonist Id2 is not expressed in pDCs, which is prominently expressed in cDCs promoting CD8+ cDC development (Spits et al. 2000; Ginhoux et al. 2009). It was found that Mtg16 restricts cDC development by repressing Id2 and promotes pDC differentiation by relieving E2-2 (Ghosh et al. 2014). A similar effect is documented for another repressor protein Zeb2 which also restricts Id2 expression to allow pDC development (Wu et al. 2016; Scott et al. 2016). Interestingly, the ETS family transcription factors ETV6 and ETS1 perform a quite similar balancing act to define pDC versus cDC fate, at least in mice. ETS1 is an inhibitor of ETV6 and both of them are expressed in mouse pDCs, while only ETV6 is expressed in in cDCs. Genetic deficiency of ETV6 drives a de-differentiation of cDC phenotype and lead to expression of genes characteristic of pDCs (Lau et al. 2018). Finally, E2-2 also was found to drive a positive feed-back loop for its own expression through a BRD protein leading to unique self-regulated identity maintenance in pDCs (Grajkowska et al. 2017).

2.3.2

IRF8

In addition, a critical role of the transcription factor IRF8 has been demonstrated in pDC development (Tailor et al. 2006). IRF8 is critical for FLT3L-activated transcription program in pDCs, counteracting the transcription program driven by GM-CSF, which drives cDC differentiation both in mice and human. In fact, GMCSF-induced phosphorylated STAT5 inhibits IRF8 transcription, thereby preventing pDC differentiation (Esashi et al. 2008). Accordingly, pDC development is deranged in mice genetically deficient in IRF8 or having a specific mutation (R294C) in IRF8, which phenocopy IRF8 gene deficiency (Tamura et al. 2005; Tailor et al. 2008). Interestingly, in a later study genetic deficiency of IRF8 was found to affect the functional phenotype in mature pDCs rather than their development (Sichien et al. 2016). Nevertheless, a more recent study verified that IRF8-expressing progenitors seem poised to differentiate into pDCs (Upadhaya et al. 2018). An important step during the course of DC development is the regulation of cell cycle persistence and exit. As expected the progenitors in the hematopoietic niche retain the capability to divide and proliferate, while as the development takes the DCs to more committed mature cells the cells exit cell cycle. A role of cMyc has been implicated in this regulation. It has been shown that the fate-determining transcription factor IRF8 drives a transition from cMyc to MycL expression

2.3

Transcriptional Program for pDC Commitment and Function

17

following the progenitor commitment in case of both cDC1 and pDCs (Anderson et al. 2022). In case of pDCs a upstream enhancer of IRF8 is also critically involved to affect the cMyc to MycL transition.

2.3.3

Regulators of Functional Identity

Once affiliation to the pDC lineage is accomplished, a number of transcriptional regulators define subsequent maturation and phenotype of pDCs. For example, SPIB, another ETS family transcription factor, functions to retain immature pDCs within the bone marrow (Sasaki et al. 2012). On the other hand, the Runt family transcription factor RUNX2 has been shown to be responsible for the release of mature pDCs to the periphery, by regulating the expression of the chemokine receptor CCR5 (Sawai et al. 2013). Another study also demonstrate that RUNX2 facilitates the egress of mature pDCs from bone marrow into the circulation, by regulating expression of molecules required for integrin-mediated interaction with endothelial cells as well as by downregulating another chemokine receptor CXCR4 (Chopin et al. 2016). Reduction in CXCR4 interaction with the stromal cell derived factor SDF1 in bone marrow niches is a universal cue for hematopoietic cells to migrate out of bone marrow. The major functional attribute of pDCs is rapid production of type I IFNs in response to activation of its endosomal TLRs. Naturally an intricate transcriptional regulation downstream of TLR signaling drives expression of the type I IFN genes. Among them perhaps the most critical “master” regulator is the interferon response family (IRF) transcription factor IRF7. It has been shown not only IFN-α induction downstream of TLR activation, but also TLR-independent IFN-α induction is severely compromised in mice with genetic deficiency for IRF7 (Honda et al. 2005). Accordingly a number of molecular regulators of IRF7 have been identified in pDCs, viz. SPIB, RUNX2, NFATC3, MYC (Sasaki et al. 2012; Chopin et al. 2016; Bao et al. 2016; Kim et al. 2016). An epigenetic regulator CXXC5 has been shown to recruit the DNA demethylase Tet2 to maintain hypomethylation of a CpG island in IRF7 gene thereby maintaining IRF7 expression in murine pDCs (Ma et al. 2017). Other transcription factors like IRF5 and IRF8 have also been implicated as regulators of type I IFN induction in pDCs (Dai et al. 2011; Sichien et al. 2016). Diverse epigenetic events can also be involved in regulating type I IFN induction in pDCs, which are yet to be elucidated fully. Indeed, a recent study reports that inhibition of histone deacetylases (HDAC) by a HDAC inhibitor enhance type I IFN induction in pDCs (Salmon et al. 2022). This complex transcriptional network perhaps allows the capacity of pDCs for rapid-fire type I IFN induction, at the same time avoiding undesired hyperactivation, in different pathophysiological contexts.

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2.4

2

Origin and Transcriptional Identity of Plasmacytoid Dendritic Cells

Localization and Migration of pDCs

The way pDCs develop into maturity and patrol the body is somewhat different from cDCs. The cDC precursors emigrate from the bone marrow, circulate in the blood to reach lymphoid organs and peripheral tissues, getting converted to resident and migratory cells, respectively (Shortman and Naik 2007). These cDCs are still “immature”—they sample antigens and have a low expression of MHC class II and costimulatory molecules. The resident cDCs mature in response to bona fide activation signals, while the migratory ones mature (even in the absence of activation signals in terms of TLR stimulation) when they reach the lymph node (Wilson et al. 2003; Villadangos and Schnorrer 2007). Thus resident cDCs perhaps are more specialized to respond to pathogenic contexts, while migratory DCs transport selfantigens from tissues to induce T cell tolerance in the lymph nodes (Steinman and Nussenzweig 2002; Reis e Sousa 2006). On the contrary, pDCs emigrate from the bone marrow and enter the circulation in a mature state. In the steady state, they are present in thymus and all the secondary lymphoid organs, while not that many are found in the peripheral tissues (Shortman and Naik 2007; Asselin-Paturel et al. 2003; Bendriss-Vermare et al. 2001; Summers et al. 2001). It is postulated that while pDCs do travel to different tissues, their tissue retention is rather restricted and tissue-specific, for example, they are seldom found in skin or lungs, while resident pDCs are quite in abundance in the intestine and kidneys (de Heer et al. 2004; Wollenberg et al. 2002; Wendland et al. 2007; Woltman et al. 2007). TLR stimulation and activation of pDCs (which will be discussed in detail in the next chapter) cause pDC accumulation in the tissues with the dominant TLR-ligand source and the draining lymph nodes. Likewise, pDCs have been reported to recruit to human or mouse skin on being treated with the TLR7 ligand imiquimod or in the cutaneous autoimmune context in psoriasis (Urosevic et al. 2005; Albanesi et al. 2009), to the lungs and mediastinal lymph nodes in mice infected with influenza or respiratory syncytial virus (Smit et al. 2006), in the footpad in mice infected with herpes simplex virus 1 (Smith et al. 2003), in the vaginal mucosa of mice infected with herpes simplex virus 2 (Palamara et al. 2004; Urosevic et al. 2005; Lande et al. 2007; GeurtsvanKessel et al. 2008; Smit et al. 2006; Shen and Iwasaki 2006). Most of the tissue-accumulated pDCs that migrate to the draining lymph nodes do so through the high endothelial venules (Yoneyama et al. 2004), but very few of them migrate and that too much later after the onset of initial activatory assault and tissue recruitment (GeurtsvanKessel et al. 2008). PDCs express a number of different chemokine receptors which they differentially utilize to migrate in different patho-physiologic and tissue contexts (Penna et al. 2001). In brief, the progenitor differentiates within the bone marrow niche employing CXCR4, emigrates out of the bone marrow employing CCR2 or CCR5, migrates in the steady state throughout the body employing CCR2 and for different tissue recruitments employ chemokine receptors such as CXCR3, CMKLR1, CCR6, CCR7, CCR9, and CCR10 (Swiecki et al. 2017; Chen et al. 2010; Ghosh et al. 2016;

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Umemoto et al. 2012; Sisirak et al. 2011; Seth et al. 2011). These will be reiterated in respective chapters while describing the role of pDCs in such varied contexts.

2.5

Conclusions

Research targeted at elucidating the developmental origin of pDCs has revealed the intricate details of differential progenitor sourcing and molecular regulations of both the DC subsets. It also revealed potential for progenitor plasticity, which is unique for pDCs among the immune cells, at least till now. The commitment to pDC lineage as well as the functional attributes are tightly regulated through specialized transcriptional programs, which in turn are tuned by a number of transcriptional regulators. Thus a combination of plasticity and lineage commitment at the transcriptional level is a unique speciality for pDCs.

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Tailor P, Tamura T, Ozato K (2006) IRF family proteins and type I interferon induction in dendritic cells. Cell Res 16(2):134–140. https://doi.org/10.1038/sj.cr.7310018 Tailor P, Tamura T, Morse HC 3rd, Ozato K (2008) The BXH2 mutation in IRF8 differentially impairs dendritic cell subset development in the mouse. Blood 111(4):1942–1945. https://doi. org/10.1182/blood-2007-07-100750 Tamura T, Tailor P, Yamaoka K, Kong HJ, Tsujimura H, O’Shea JJ, Singh H, Ozato K (2005) IFN regulatory factor-4 and -8 govern dendritic cell subset development and their functional diversity. J Immunol 174(5):2573–2581. https://doi.org/10.4049/jimmunol.174.5.2573 Umemoto E, Otani K, Ikeno T, Verjan Garcia N, Hayasaka H, Bai Z, Jang MH, Tanaka T, Nagasawa T, Ueda K, Miyasaka M (2012) Constitutive plasmacytoid dendritic cell migration to the splenic white pulp is cooperatively regulated by CCR7- and CXCR4-mediated signaling. J Immunol 189(1):191–199. https://doi.org/10.4049/jimmunol.1200802 Upadhaya S, Sawai CM, Papalexi E, Rashidfarrokhi A, Jang G, Chattopadhyay P, Satija R, Reizis B (2018) Kinetics of adult hematopoietic stem cell differentiation in vivo. J Exp Med 215(11): 2815–2832. https://doi.org/10.1084/jem.20180136 Urosevic M, Dummer R, Conrad C, Beyeler M, Laine E, Burg G, Gilliet M (2005) Diseaseindependent skin recruitment and activation of plasmacytoid predendritic cells following imiquimod treatment. J Natl Cancer Inst 97(15):1143–1153. https://doi.org/10.1093/jnci/dji207 Villadangos JA, Schnorrer P (2007) Intrinsic and cooperative antigen-presenting functions of dendritic-cell subsets in vivo. Nat Rev Immunol 7(7):543–555. https://doi.org/10.1038/nri2103 Waskow C, Liu K, Darrasse-Jèze G, Guermonprez P, Ginhoux F, Merad M, Shengelia T, Yao K, Nussenzweig M (2008) The receptor tyrosine kinase FLT3 is required for dendritic cell development in peripheral lymphoid tissues. Nat Immunol 9(6):676–683. https://doi.org/10. 1038/ni.1615 Wendland M, Czeloth N, Mach N, Malissen B, Kremmer E, Pabst O, Förster R (2007) CCR9 is a homing receptor for plasmacytoid dendritic cells to the small intestine. Proc Natl Acad Sci U S A 104(15):6347–6352. https://doi.org/10.1073/pnas.0609180104 Wilson NS, El-Sukkari D, Belz GT, Smith CM, Steptoe RJ, Heath WR, Shortman K, Villadangos JA (2003) Most lymphoid organ dendritic cell types are phenotypically and functionally immature. Blood 102(6):2187–2194. https://doi.org/10.1182/blood-2003-02-0513 Wollenberg A, Wagner M, Günther S, Towarowski A, Tuma E, Moderer M, Rothenfusser S, Wetzel S, Endres S, Hartmann G (2002) Plasmacytoid dendritic cells: a new cutaneous dendritic cell subset with distinct role in inflammatory skin diseases. J Invest Dermatol 119(5): 1096–1102. https://doi.org/10.1046/j.1523-1747.2002.19515.x Woltman AM, de Fijter JW, Zuidwijk K, Vlug AG, Bajema IM, van der Kooij SW, van Ham V, van Kooten C (2007) Quantification of dendritic cell subsets in human renal tissue under normal and pathological conditions. Kidney Int 71(10):1001–1008. https://doi.org/10.1038/sj.ki.5002187 Wu X, Satpathy AT, Kc W, Liu P, Murphy TL, Murphy KM (2013) Bcl11a controls FLT3 expression in early hematopoietic progenitors and is required for pDC development in vivo. PLoS One 8(5):e64800. https://doi.org/10.1371/journal.pone.0064800 Wu X, Briseño CG, Grajales-Reyes GE, Haldar M, Iwata A, Kretzer NM, Kc W, Tussiwand R, Higashi Y, Murphy TL, Murphy KM (2016) Transcription factor Zeb2 regulates commitment to plasmacytoid dendritic cell and monocyte fate. Proc Natl Acad Sci U S A 113(51): 14775–14780. https://doi.org/10.1073/pnas.1611408114 Yoneyama H, Matsuno K, Zhang Y, Nishiwaki T, Kitabatake M, Ueha S, Narumi S, Morikawa S, Ezaki T, Lu B, Gerard C, Ishikawa S, Matsushima K (2004) Evidence for recruitment of plasmacytoid dendritic cell precursors to inflamed lymph nodes through high endothelial venules. Int Immunol 16(7):915–928. https://doi.org/10.1093/intimm/dxh093 Zhan Y, Chow KV, Soo P, Xu Z, Brady JL, Lawlor KE, Masters SL, O’keeffe M, Shortman K, Zhang JG, Lew AM (2016) Plasmacytoid dendritic cells are short-lived: reappraising the influence of migration, genetic factors and activation on estimation of lifespan. Sci Rep 6: 25060. https://doi.org/10.1038/srep25060

Chapter 3

Activation and Functions of Plasmacytoid Dendritic Cells

The major functional identity of plasmacytoid dendritic cells (pDCs), despite their ontogenic affiliation to the dendritic cell (DC) lineage of professional antigen presenting cells (APCs), is defined by rapid and massive induction of type I interferon family of cytokines (type I IFNs) in response to pathogens, mostly viruses. This functional identity is cell biologically defined by the presence of toll-like receptors (TLRs) TLR7 and TLR9 in the endo-lysosomal compartments of pDCs (Gilliet et al. 2008; Ganguly 2018; Lind et al. 2022). TLR7 recognizes single stranded RNA (ssRNA) molecules, while TLR9 recognizes unmethylated CpG motifs in single/double stranded DNA (ss/dsDNA) molecules, ligands which are present in cells from across the tree of life. Naturally these TLRs, as well as three other nucleic acid-sensing TLRs, viz. TLR3 (recognizes double stranded RNA), TLR8, and TLR13 (recognizes ssRNA), have the potential to react to both pathogens as well as the host origin ligands. The major outcome of the endosomal TLR activation in pDCs is induction of type I IFNs, while it also leads to induction of proinflammatory cytokines, mostly TNF-α and IL-6 and drive expression of MHC class II molecules and several costimulatory molecules on pDC cell surface. Thus activated pDCs assume their antigen presentation function as well, being true to their ontogenic indentity, and drive T cell priming (Gilliet et al. 2008; Reizis et al. 2011). In this chapter, we will discuss the cell biological and biochemical specialties of the TLR activation in pDCs, the major functional attributes of an activated pDC and the pDC-intrinsic regulatory modules and mechanisms that are critical for the physio-pathological roles played by pDCs.

3.1

Toll-like Receptor Activation and Signaling in pDCs

Unlike conventional DCs (cDCs), pDCs are known to express only TLR7 and TLR9, at least in the resting state (Kadowaki et al. 2001). On the other hand, in humans TLR7 and TLR9 expression is known to be restricted to only pDCs and B © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 D. Ganguly, Plasmacytoid Dendritic Cells, https://doi.org/10.1007/978-981-19-5595-2_3

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cells, again perhaps assuming resting state for all different immune cells (Hornung et al. 2002). Of note, in mouse cDCs also express TLR7 and TLR9, apart from other TLRs like TLR1, TLR2, TLR3, TLR4, TLR5, TLR8 (Kadowaki et al. 2001). In specific inflammatory contexts this characteristic expression has been shown to differ, for example, expression of TLR2 and its role in specific contexts has recently been reported in pDCs (Raieli et al. 2019; van der Sluis et al. 2022). Nevertheless, the major functional attributes of human pDCs are critically dependent on TLR7 and TLR9 signaling. Toll-like receptors that are specialized for nucleic acid ligand recognition show shared structural features, especially an intraluminal/extracellular leucine-rich-repeat (LRR) domain, which actually binds the ligands ligand, a transmembrane helical part and the cytosolic Toll/IL-1 receptor (TIR) domain, which is shared amongst most TLRs. Dimerization of TLRs in response to ligand binding drives downstream signaling. TLR7 activation ensues on recognizing single-stranded RNA (ssRNA) ligands with at least one guanosine (G) nucleoside at the first ligand-binding site and a ssRNA trimer that contains a uridine dimer (UUX) at the second ligand-binding site (Zhang et al. 2016, 2018). Though the ligand recognized by TLR8 (expressed by cDCs) is also ssRNA, but it has been shown that it rather binds uridine in the first binding site, while the second site binds UG dimers (Tanji et al. 2013, 2015). For TLR9 activation unmethylated CpG motifs within a DNA strand to be recognized is critical (Ohto et al. 2015). The second site in TLR9 binds a 5′-XCX motif in DNA and promotes receptor dimerization along with the CpG motif bound to the first site (Ohto et al. 2018). It has been proposed that ligand characteristics, especially for the CpG motif, that drive maximal activation of TLR9, differ among species (Bauer et al. 2001). Over past two decades a general model of signal transduction downstream of TLR activation through binding of cognate ligands has been developed (Akira and Takeda 2004; Honda and Taniguchi 2006; O’Neill and Bowie 2007). According to the simplified general model the signaling cascade following TLR activation is initiated by recruitment of a family of adaptor proteins, viz. myeloid differentiation primary response protein 88 (Myd88), TIR domain-containing adaptor protein (TIRAP), TIR domain-containing adaptor protein inducing IFNβ (TRIF or TICAM1), and TRIF-related adaptor molecule (TRAM or TICAM2). The adapter proteins bind to the TIR domain in the cytoplasmic or extraluminal (in case of the endosomal TLRs like TLR7 or TLR9). Almost all TLRs initiate signaling by recruiting MYD88, except TLR3 that recruits TRIF and TLR4 that can recruit both Myd88 and TRIF. The signaling events downstream of the adapter recruitment mostly involve activation and nuclear translocation of nuclear factor-κB (NFκB), interferonregulatory factors (IRFs), and a few other more pleiotropic transcription factors. In addition to recognizing distinct cognate ligands, individual TLRs also differ in terms of triggering different signaling pathways and distinct transcriptional programs. While TLR3, TLR4, TLR7, TLR9 can induce transcriptional programs leading to production of pro-inflammatory cytokines as well as type I IFNs, others like TLR2 and TLR5 can only drive production of pro-inflammatory cytokines like TNF-α,

3.2

Cell Biology of Endosomal TLR Localization in pDCs

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IL-6, IL-8 (Kawai and Akira 2006). These are presumed to be largely driven by particular adaptors dominantly engaging particular signaling pathway, e.g. TIRAP and MYD88 activating the mitogen-activated protein kinase (MAPK) and NF-κB pathways driving pro-inflammatory cytokine induction, while TRAM and TRIF activating TANK-binding kinase 1 (TBK1) and IκB kinase-ε (IKKε) inducing type I IFN production. While the aforementioned schema largely represents a general model for TLR activation, there are deviations from these general schema for specific TLRs and the endosomal TLRs in pDCs do feature quite a few such deviations. While in general TLRs (e.g., TLR2 and TLR4) depend on TIRAP to recruit Myd88, TLR7 or TLR9 does not need it (Horng et al. 2002). On the other hand, Myd88 recruitment is unable to drive type I IFN induction downstream of most TLRs, unlike with TLR7 and TLR9 (Hemmi et al. 2003). Myd88 recruitment to TLR7 and TLR9 drive type I IFN induction by phosphorylation, nuclear translocation and transcription factor activity of IRF7. While the same event, presumably from a different endo-lysosomal compartment drive MAPK pathway triggering and NFκB activation. This in turn drives transcription of genes for the pro-inflammatory cytokines, mostly TNF-α, IL-6 and perhaps also IL-8 and promote higher surface expression of MHC class I and class II molecules and CD80 (activatory), PDL1 (inhibitory) and few other costimulatory molecules, with variable effects on T cells (Gilliet et al. 2008; Ganguly et al. 2013). Thus on TLR activation pDCs, apart from accomplishing its specialized function of type I IFN production, assume a functional phenotype quite akin to cDCs. Indeed, even a change in the cell surface morphology of pDCs have been documented in response to TLR activation, becoming more cDC-like with dendritic processes, which is also associated with a reduction in the expression of the pDC-identitydefining transcription factor E2-2 and increase in expression of ID2, known to drive cDC identity (Cisse et al. 2008; Ghosh et al. 2010).

3.2

Cell Biology of Endosomal TLR Localization in pDCs

As the endosomal TLRs in pDCs are able to recognize nucleic acid ligands, which can be of both pathogenic and host origin, a number of cell biological peculiarities in the regulation of spatial localization of these TLRs might have provided natural contraptions to prevent undesired immune activation, for example, in response to innocuous molecular entities with ability to trigger the TLRs as well as to selfnucleic acid molecules encountered in the extracellular space due to physiological cellular turn-over in tissues. The endosomal localization itself may serve a similar purpose, whereby access of potential ligands to the TLRs is rather restricted and regulated (Lind et al. 2022). Whether individual TLRs reside within specific and exclusive endo-lysosomal compartments still remains unestablished. Even studies on endosomal localization of these TLRs initially varied in their conclusions, mentioning different compartments like early endosomes, late endosomes, multivesicular bodies, lysosomes, the endoplasmic reticulum (ER), and even the

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plasma membrane (Häcker et al. 1998; Latz et al. 2004; Leifer et al. 2004; Ewaschuk et al. 2007). Perhaps these discrepancies was because of the dynamic evolution of the membrane-bound compartments within the cells and the intricate regulation of TLR localization in the endo-lysosomal compartment which was revealed later. Research on intracellular localization of the endosomal TLRs mostly focused on TLR9. The cell biology of TLR7 localization should not be very different though. Biochemical studies on TLR9 revealed that a proteolytically processed (cleaved) form of the receptor (with the amino terminal part of the ectodomain removed) is present in the endolysosomal compartments (Ewald et al. 2008; Park et al. 2008). On analyzing the glycosylation of TLR9 also revealed that the processed receptor passes through golgi complex before reaching the endo-lysosomal compartments. The ER-resident TLR9 is the unprocessed full length protein, which is processed within the golgi. A similar proteolytic processing of TLR7 in golgi has also been reported (Ewald et al. 2008; Barton and Kagan 2009). Only the processed TLR9 was found to bind its ligands as well as to bind the adapter Myd88. While the specific proteases responsible for TLR7 and TLR9 processing are not known, inhibitors of cathepsin B, cathepsin L, and cathepsin K block TLR9 signaling. Several lysosomal proteases has been shown to cleave TLR9 in vitro to generate a processed receptor, pointing to a redundant role of such proteases for the TLR-processing function (Ewald et al. 2008). In a more recent study inhibition of endosomal acidification has been shown to interfere with TLR7 proteolytic processing as well (Cenac et al. 2022). UNC93B1, a 12-membrane-spanning ER protein, has been found to regulate the trafficking of the translated TLR proteins through the different compartments (Tabeta et al. 2006; Kim et al. 2008). In mice genetically deficient in UNC93B1, endosomal TLR activation is defective (Brinkmann et al. 2007). In a recent study it has been shown that UNC93B1 may also function to regulate expression of the TLRs (Pelka et al. 2018). Figure 3.1 depicts the intracellular maturation and localization process of the endosomal TLRs in pDCs.

3.3

The Cytokine Response in pDCs in Response to TLR Activation

As the original name of pDCs and our discussion at length in this volume suggests, the major outcome of TLR activation in pDCs is the induction of type I IFNs (Gilliet et al. 2008; Ganguly et al. 2013). Interferons (IFNs) were originally discovered in the 1950s and were named so to indicate their ability to “interfere” with viral replication in infected host cells, as described earlier. There are three classes of IFNs, named type I, II, and III IFNs and they bind to and initiate intracellular signaling through distinct heterodimeric receptors that induce the Janus kinase–signal transducer and activator of transcription (JAK–STAT) signaling pathway, which in turn drives characteristic gene expression. Human type I IFNs comprise of 13 subtypes of IFN-α, IFN-β, IFN-ε, and IFN-ω (Mesev et al. 2019). The type II IFN has the single

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The Cytokine Response in pDCs in Response to TLR Activation

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Fig. 3.1 Intracellular trafficking and proteolytic processing of the endosomal toll-like receptors in plasmacytoid dendritic cells. Endosomal toll-like receptors in plasmacytoid dendritic cells (TLR9 and TLR7) after their translation in endoplasmic reticulum, take a passage through Golgi network and trafficked to the endo-lysosomal compartments, aided by the chaperone protein UNC93B1. Within endo-lysosomal compartments the TLR molecules are proteolytically processed to derive the mature receptors able to bind to ligands as well as the signaling adapters. (Reproduced with permission from Barton GM and Kagan JC, 2009)

member IFN-γ and type III IFNs has four members (IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4). PDCs also produce type III IFNs in contexts of viral infections (Yun et al. 2021). There is no evidence for induction of type II IFN in pDCs. Only three cell surface IFN receptors being expressed in different combinations recognize almost 20 members from three types of IFNs. The receptor for the type I IFNs (IFNAR) is composed of the subunits IFNAR1 and IFNAR2. The receptor for the type II IFN (IFNGR) is composed of the subunits IFNGR1 and IFNGR2. The receptor for the type III IFN (IFNLR) is composed of the subunits IFNLR1 and IL-10Rβ, with one subunit shared with receptor for the immunoregulatory cytokine IL-10. IFNAR is present on practically all nucleated cell types, while IFNLR is perhaps restricted mainly to epithelial cells and neutrophils. IFN binding to the receptor complex leads to cross-phosphorylation of JAK1 and TYK2 on the

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Fig. 3.2 Type I and type II interferon signaling. The different family members of type I and type II interferons, released by activated plasmacytoid dendritic cells, the receptor subunit combinations used by them, the downstream signaling molecules employed on receptor activation, and the eventual transcriptional response are shown schematically. (Reproduced with permission from Mesev EV, 2019)

cytoplasmic domains of the receptor, which in turn triggers phosphorylation of STAT1 and STAT2 (Fig. 3.2). The phosphorylated STATs form combinatorial complexes, translocate to nucleus and bind either the IFN-stimulated response elements (ISREs) or gamma-activated sequences (GAS) on the promoters of target genes. Activation of these promoter elements transcribes hundreds of genes involved particularly in antiviral response, genes of a group of chemokines as well as regulatory genes that are integral to and thus amplify the IFNAR signaling pathway. There is a characteristic family of genes which are tell-tale signs of IFNAR activation and in different patho-physiological contexts can function as surrogates for type I IFN induction in situ. The family is called interferon signature genes or ISGs (viz. MX1 MX2, ISG15, IRF7, IFIT1, TRIP14, etc.).

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The Cytokine Response in pDCs in Response to TLR Activation

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In pDCs, IRF7 phosphorylation downstream of TLR activation drives the transcription of the IFN genes. On the other hand, the activation of pDCs is also modulated by action of these cytokines on the IFNAR expressed on pDC cell surface. While the initial rapid induction of type I IFNs following TLR activation in pDCs has been linked to steady-state expression of IRF7, a second phase of type I IFN induction, that enables a sustained IFN response in activated pDCs, has been linked to activation of IFNAR on pDCs themselves (Izaguirre et al. 2003; Kerkmann et al. 2003; Kim et al. 2014). On the other hand in the context virus infection the type I IFN response in pDCs have been shown to be independent of IFNAR signaling (Barchet et al. 2002). It has been reported that while resting pDCs do not express the cytosolic sensor RIG-I that also can induce a type I IFN response, as it does in other innate immune cells like macrophages, in response to both TLR activation and IFNAR signaling there is expression of RIG-I in pDCs (Szabo et al. 2014). Thus the sustained type I IFN response in pDCs may also lead from a secondary activation of RIG-I signaling in later timepoints, which may also play a major role in case of virus-infected pDCs (Kumagai et al. 2009). In addition to type I IFNs, as discussed already, endosomal TLR activation drive transcription of genes for a number of pro-inflammatory cytokines, in a MAPK pathway and NFκB-dependent manner. The major pro-inflammatory cytokines produced, in response to TLR9 activation by B type CpG oligonucleotides and TLR7 activation by either ssRNA ligands or small molecule agonists like imiquimod or R848, are TNF-α, IL-6, and IL-8. Interestingly, TLR9 activation with A type CpG oligonucleotides fail to induce considerable NFκB activation, and as a result significant production of pro-inflammatory cytokines (Honda et al. 2005), which we will further discuss in a later section here. In a recent study mass spectrometry-based exploration was attempted for gaining insight into the diversity and relative content of different secreted proteins (the total secretome) of human pDCs ex vivo, in resting condition as well as in response to exposure to H1N1 influenza, a single-stranded RNA virus (Ghanem et al. 2022). As expected all members of the type I and type III IFNs and the proinflammatory cytokines TNF-α and IL-6 were the dominant cytokines released by the activated pDCs in the supernatant. In addition, a number of chemokines like CCL4, CCL19, CXCL9, and CXCL10 (last two being driven by type I IFN signaling directly) as well as several secretory proteins known to be bona fide ISGs (viz. ISG15, SRGN) were, as expected, part of the pDC secretome. Interestingly, the secretome of the activated pDCs also included lysosomal cysteine proteases cathepsin c and cathepsin z, the asparaginyl endopeptidase legumain as well as the transcription factor IRF8 and cytotoxic protein granzyme B. Thus the in vivo functional potential of pDC secretome in response to viral infections as well as in other contexts warrants further exploration.

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Antigen Presentation by pDCs

Type I IFNs produced by pDCs in response to TLR activation in turn promote both the innate (e.g., by activating natural killer cells as well as cDCs) and the adaptive (e.g., by acting on B cells) immune responses. But the concomitant upregulation of MHC class I and class II molecules as well as the costimulatory molecules also enable activated pDCs to play a direct role in antigen presentation to T cells and thus priming and activating them (Gilliet et al. 2008). Comparison of localization and migration of pDCs and cDCs in the context of infection or inflammation, as discussed in the last chapter, indicates a more plausible role of pDCs in antigen presentation at the very sites of infection or inflammation. CDCs seem much more specialized for the function of antigen transport to the draining lymph nodes for T cell priming. Recruitment of pDCs to the draining lymph nodes may rather serve to maintain a pro-inflammatory milieu, through its type I IFN induction function (Villadangos and Young 2008). It is established that pDCs can prime both naïve and memory T cells, as they undergo maturation (Colonna et al. 2004). As a support to this, it has been reported that pDCs can stimulate and sustain immunity when adoptively transferred (Salio et al. 2004). Just like cDCs, pDCs can induce antigen-specific T cell tolerance, and drive generation of regulatory T cells (Gilliet and Liu 2002; Ito et al. 2007). On the other hand, it is also established that pDCs are much less efficient compared to cDCs at T cell priming, express much less MHC molecules (both class I and class II) on their surface compared to cDCs, even on activation. It is assumed that pDCs rather lack in their ability to prime T cells with exogenous antigens, which are either presented on MHC class II molecules or cross-presented on MHC class I molecules (Villadangos and Young 2008). Efficiency of pDCs in presenting endogenous antigens via MHC I and II molecules has been demonstrated in several studies, in case of constitutively expressed self-antigens as well as for antigens expressed following viral infection of pDCs (Krug et al. 2003; Fonteneau et al. 2003; Salio et al. 2004; Young et al. 2008). The relative deficiency in pDCs for priming T cells with exogenous antigens may have to do with some or all of the following properties. The lower expression of MHC molecules as well as weaker ability of phagocytosis may stoichiometrically deter pDCs from efficiently presenting relatively less abundant exogenous antigens. PDCs are much less phagocytic than cDCs. While cDCs can efficiently internalize extracellular dead cell debris, proteins or intact pathogens by macropinocytosis, phagocytosis, and receptor-mediated endocytosis, inability of pDCs to phagocytose dead cells, zymosan, or artificial particles are documented (Dalgaard et al. 2005; Grouard et al. 1997; Stent et al. 2002). Evidences on the contrary are also not rare (Ochando et al. 2006). PDCs do internalize soluble proteins (e.g., experimental antigens ovalbumin, hen egg lysozyme) efficiently, perhaps by pinocytosis or receptor-mediated endocytosis (de Heer et al. 2004; Young et al. 2008). A number of cell surface molecules in pDCs (some of which will be discussed in more detail later in the chapter) have been implicated to mediate

3.5

Cell Biology of Differential pDC Response to TLR Activation

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the receptor-mediated endocytotic events, viz. the C-type lectin receptors BDCA-2, Siglec-H, DCIR, and the immunoglobulin γ Fc receptor CD32. The efficiency of cDCs for presentation of exogenous antigens depends to a great extent on ability to retain MHC II-peptide complexes on their cell surface longer (Villadangos et al. 2005). The density of MHC II-peptide complexes on cDC cell surface does not change much as recruitment of new complexes is matches the kinetics of endocytosis as well as degradation of pre-existing complexes by MHC II β chain ubiquitination by the ubiquitin ligase March I (Villadangos et al. 2005; Shin et al. 2006; De Gassart et al. 2008). Similar sustenance of the MHC II-peptide complexes do not occur in pDCs preventing them from efficiently presenting limiting amounts of exogenous antigens (Villadangos and Young 2008). Finally, a major property that makes cDCs professional APCs is their ability to present exogenous antigens on MHC I molecules, i.e. to cross-present. While specific subsets of cDCs appear to be variably capable of cross-presentation, in case of pDCs the evidence is really equivocal (Pooley et al. 2001; Villadangos and Young 2008). For mouse pDCs an inability for cross-presentation is reported a number of studies (Salio et al. 2004; Sapoznikov et al. 2007). On the other hand with human pDCs some evidence of cross-presentation ability for specific antigens, especially antigens embedded within immune complexes has been reported (Schnurr et al. 2005; Di Pucchio et al. 2008). Thus specific receptor mediated endocytosis events may enable pDCs to crosspresent certain antigens, but that does not make them as efficient in such functions as cDCs.

3.5

Cell Biology of Differential pDC Response to TLR Activation

TLR7 and TLR9 on encountering their ligands in the endosomal vesicles recruit MyD88, which leads to induction of NF-kB-dependent proinflammatory cytokines as well as IRF7-dependent type I IFNs. More interestingly, the endosomal compartments initiating these two signaling pathways are thought to be different. Thus spatio-temporal regulation of the TLR-ligand interaction influences the relative dominance of these two pathways (Honda et al. 2005; Gilliet et al. 2008). As the biological outcomes of these two signaling pathways are very different—activation of NF-κB drives transcription of genes for the proinflammatory cytokines (e.g., IL-6 and TNF-α), while activation of IRF7 drives transcription of the type I IFN genes, the regulation of pDC endosomal trafficking is a key determinant of functional potential of pDCs in different physiological and pathological contexts. Interestingly, in case of TLR9 differences in structural attributes of the ligands seem to affect this spatio-temporal regulation of TLR activation to a great extent. Type A CpG sequences have been shown to be retained longer in the early endosomes and outcome of TLR9 activation by these ligands is dominated by nuclear translocation of IRF7 and induction of type I IFN induction, with little or

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Fig. 3.3 Spatio-temporal regulation of TLR9 activation in plasmacytoid dendritic cells. TLR9 activation from the early endosomal compartments of plasmacytoid dendritic cells drives a predominant IRF7 activation and nuclear translocation inducing type I interferons. On the other hand, TLR9 activation from the late endosomal or lysosomal compartments in plasmacytoid dendritic cells leads to a predominant NFκB activation and nuclear translocation driving production of pro-inflammatory cytokines. (Reproduced with permission from Gilliet M et al., 2008)

no induction of NF-kB activation and proinflammatory cytokine production (Honda et al. 2005). On the other hand, type B CpG sequences are faster trafficked to lysosomes and TLR9 activation in this case is rather dominated by NF-kB activation and proinflammatory cytokine production (Fig. 3.3). Data from other studies recapitulated this differential TLR9 activation in the context of host-derived nucleic acid molecules. As described earlier, self-nucleic acid molecules, either dsDNA or ssRNA, can bind to proteins like HMGB1 and TFAM or antimicrobial peptides like LL-37 and defensins, to gain access to the pDC endosomes and interact therein with the respective TLRs (Ganguly et al. 2009; Ghosh et al. 2016; Julian et al. 2012). It has been shown that in case of antimicrobial peptides like LL-37 and defensins, these self-nucleic acid-protein complexes are also retained longer in the early endosomes and thus drive dominant IRF7 activation and finally type I IFN induction (Lande et al. 2007; Ganguly et al. 2009). This differential regulation of the endosomal trafficking of the TLR-ligand cargo is an active area of research in pDC biology. A number of regulatory molecules have

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Cell Biology of Differential pDC Response to TLR Activation

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been implicated in this phenomenon. For example, PACSIN1 (protein kinase C and casein kinase substrate in neurons 1) was found to regulate this differential downstream signaling from TLR7 and TLR9. PACSIN1 expression is enriched in both human and mouse pDCs and deficiency in this protein selectively inhibits type I IFN induction, while not affecting induction of proinflammatory cytokines downstream of TLR activation (Esashi et al. 2012). Wiskott-Aldrich syndrome protein (WASP), a regulator of actin dynamics in hematopoietic cells, has also been implicated as a regulator of type I IFN induction by pDCs—a mutation in this protein, which causes the syndrome that it derives its name from, leads to increase in the type I IFN induction in response TLR9 ligand (Prete et al. 2013). WASP is also presumed to regulate differential compartmentalization of TLR9-ligand interaction in pDCs. In a more recent study SIDT1, a mammalian ortholog of the SID-1 dsRNA transporter of Caenorhabditis elegans has been shown to regulate type I IFN induction in pDCs. The other close member of this protein family, SIDT2, is expressed in the endolysosomal compartments and has been shown to be critical for cytosolic release of double stranded RNA cargo to affect activation of cytosolic RNA sensors like RIG-I like receptors (RLRs). Mice genetically deficient in SIDT2 show less survival in response to HSV type 1 (HSV-1) virus (Nguyen et al. 2017). But the role of SIDT1 in this dsRNA transport function is known to be not dominant, at least in mice, and animals deficient in SIDT1 do not succumb to HSV-1 infection either (Nguyen et al. 2019). Interestingly, SIDT1 is enriched in expression in the pDCs and its deficiency renders pDCs unable to produce type I IFNs in response to TLR9 activation (Morell et al. 2022). SIDT1 accompanies TLR9 on its way from the ER to the endolysosomal compartments in response to CpG stimulation and help the TLR9-CpG complex to access endosomal compartments associated with IRF7 activation, but not with NF-kB activation. In a forward genetics screen, for identifying genes essential for pDC development, identity and function a mutation named ‘feeble’ was mapped to the gene SLC15A4. SLC15A4 encodes for the peptide/histidine transporter 1 (PHT1) and the mutation was found to abrogate type I IFN and proinflammatory cytokine production by pDCs in response to endosomal TLR Activation (Blasius et al. 2010). Interestingly, TLR signaling and response in other immune cells were not affected by the SLC15A4 mutation. The mutational phenotype also led to the identification of AP-3 (represented by the “pearl” mutation) and the Hermansky-Pudlak syndrome protein complexes BLOC-1 (represented by the “salt and pepper” mutation in dysbindin, a component of BLOC-1) and BLOC-2 (represented by the “toffee” allele of HPS5, a component of the BLOC-2 complex) as essential regulators for TLR9 and TLR7 signaling in mouse pDCs, but not in cDCs, which in mouse also expresses these two TLRs. It is proposed that these pDC-specific regulators may also control the endosomal dynamics in pDCs, thereby influencing TLR activation. Of note here, uptake of the TLR ligands, viz. CpGA, was not affected by this mutation, implicating its role further downstream, presumably in the functionality of the endolysosomal compartment.

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3.6

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Cellular Metabolism of Activated pDCs

Recent interests in the domain of immunometabolism have established that immune cells feature alterations in their cellular metabolic pathways during steady state, functional differentiation or activation (O’Neill et al. 2016). Similarly functional attributes of dendritic cell subsets are also closely linked to cellular metabolism (Pearce and Everts 2015). In mouse bone marrow-derived cDCs (BMDCs) in the resting state use of fatty acid oxidation to fuel oxidative phosphorylation has been documented (Krawczyk et al. 2010). The cellular metabolism in resting cDCs and pDCs, both in humans and mice are also expected to employ catabolism of complex molecules to cater for substrates for the Kreb’s cycle. Especially the requirement of rapid response to TLR ligands and ramping up protein synthesis require, not only in DCs, but also in almost all immune cells, to maintain glycolytic integrity, mitochondrial health as well as fatty acid oxidation pathways at the same time (Pearce and Everts 2015). In response to TLR activation with an increased demand for ATP, a glycolytic switch, with pyruvate being converted predominantly to lactate, is encountered, not only in mouse BMDCs but also in most other diverse-origin DC subsets (Wculek et al. 2019; Saas et al. 2017; Everts et al. 2014). This pyruvate to lactate conversion leads to a coupled regeneration of NAD+ and ATP generation from glycolysis, providing source for ATP in hypoxic conditions using glucose, instead of fatty acids or amino acids. In response to viral infection, viz. influenza and rhinovirus, human pDCs have been shown to depend upon glycolysis for type I IFN induction and phenotyping maturation (Bajwa et al. 2016). Exposure to these RNA viruses, which are recognized by TLR7 in pDCs, leads to activation of HIF-1α, which is critical for the glycolytic switch as it regulates expression of a number of key glycolytic enzymes, viz. hexokinase and phosphofructokinase. TLR7 activation induces rapid switch over to glycolysis in human PDC, leading to lactate secretion in extracellular milieu. Inhibition of glycolysis by adding the glycolytic inhibitor 2-deoxyglucose (2-DG) severely reduces pDC activation in response to TLR7 ligands, in terms of type I IFN induction as well as the upregulation of MHC class II molecules, and costimulatory molecules. Regarding a similar metabolic response to TLR9 stimulation there are contradictory evidences, with one study reporting a delayed glycolytic switch in mouse pDCs, while another recording an early increase in glycolysis in human pDCs (Wu et al. 2016; Raychaudhuri et al. 2019). In the later study accumulation of lactate in the extracellular milieu thwarted this metabolic change in human pDCs in response to TLR9 activation and abrogated type I IFN induction. The mammalian target of rapamycin (mTOR), a serine-threonine protein kinase serving as the catalytic entity of mTORC1 and mTORC2 enzyme complexes, senses nutrient and oxygen availability to integrate different metabolic pathways. For example, mTORC1 drives glycolysis through hypoxia-inducible factor 1α (HIF-1α) and the cholesterol and fatty acid synthesis pathways utilizing intermediate metabolites of TCA cycle (Weichhart et al. 2015; Sukhbaatar et al. 2016).

3.6

Cellular Metabolism of Activated pDCs

37

Cholesterol and fatty acids are critical for maturation of endoplasmic reticulum and Golgi apparatus, organelles that in turn regulate cytokine secretion. It has been shown that even resting pDCs show a constitutive activation of mTOR and inhibition of mTOR led to abrogation of type I IFN induction in both human and mouse pDCs, in response to both TLR9 and TLR7 ligands (Cao et al. 2008). Inhibition of mTOR was found to prevent TLR9-Myd88 interaction preventing IRF7 activation and translocation to the nucleus. As expected, inhibiting Pi3K, upstream of mTOR activation, also inhibits pDC activation (Cao et al. 2008; Guiducci et al. 2008). Development of mouse pDCs in FLT3L cultures is also critically dependent on mTOR signaling. The mTOR inhibitor rapamycin has been shown to impair pDC development, while deletion of the phosphoinositide 3-kinase (PI3K)-mTOR negative regulator or PTEN facilitates FLT3L-driven pDC development (Sathaliyawala et al. 2010). Interestingly, apart from pDC development and TLR-driven activation, pDC-driven generation of Tregs also seem to be dependent on mTOR (Biswas et al. 2015). Mouse PDC activation in response to TLR9 ligand CpGA exhibit a concomitant increase in basal oxygen consumption rate (OCR) and spare respiratory capacity (SRC), which indicate an increase in fatty acid oxidation as etomoxir, the inhibitor of carnitine palmitoyl transferase I (enzyme driving entry of activated fatty acids into mitochondria for oxidation), inhibits both the increase of basal OCR and SRC (Wu et al. 2016). Etomoxir also reduces production of IFN-α and pro-inflammatory cytokines (TNF-α and IL-6) as well as costimulatory molecule expression by mouse pDCs in response to TLR9 activation. A role of autocrine or paracrine action of type I IFNs on the IFNAR receptor on pDCs themselves has also been implicated in the induction of fatty acid oxidation as IFN-α alone can also drive the same in the absence of TLR stimulation (Wu et al. 2016). Moreover, the metabolic state of mouse pDCs in response to IFN-α is associated with increased cellular ATP, which in turn is significantly reduced by inhibition of fatty acid oxidation, mitochondrial import of pyruvate or fatty acid synthesis, confirming that type I IFN stimulation of mouse pDCs significantly generates ATP through fatty acid oxidation. Keeping in mind a delay in ramping up of glycolysis in mouse pDCs and this early dependence on fatty acid oxidation for ATP generation may indicate a differential regulation of cellular respiration in mouse versus human pDCs in the context of TLR stimulation, validation of which needs further exploration of cellular respiration in human pDCs. Mitochondrial reactive oxygen species generation, an outcome of increased oxidative phosphorylation, has been shown to be detrimental to type I IFN induction by human pDCs in response to TLR activation, but not to the NF-kB-dependent induction of proinflammatory cytokines (Agod et al. 2017). Notably, the reported late-phase type I IFN induction through RIG-I, which is upregulated in response to TLR activation in human pDCs, was shown to be dependent on oxidative phosphorylation with an inhibition of glycolysis further enhancing the cytokine production (Fekete et al. 2018). Moreover, a recent study identified that unfolded protein response (UPR) in pDCs, especially mediated by the IRE1α-XBP1 pathway, also regulates IFN-α production in response to TLR activation (Chaudhary et al.

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2022). It was reported that UPR activation redirected glycolysis to serine biosynthesis and reduced pyruvate access to TCA cycle, thereby reducing mitochondrial ATP generation. Finally, statins (inhibitors of the mevalonate pathway of de novo cholesterol biosynthesis) has been shown to inhibit type I IFN production by human PDC in response to both TLR7 and TLR9 activation, also replicated in vivo in mice infected with Sendai virus (Amuro et al. 2010). Statin treatment was found to interfere with activation of p38 MAPK pathway, phosphorylation of AKT, and phosphorylation and nuclear translocation of IRF7 in pDCs. On the other hand, human pDCs have been shown to express liver X receptor (LXR) that drives cholesterol efflux from the cells and LXR activation in pDCs have shown to inhibit production of TNF-α and IL-6 by interfering with NFκB activation (Ceroi et al. 2016). The seemingly counterintuitive finding of differential pDC activation in response to increased cholesterol synthesis and increased cholesterol efflux may gather some reconciliatory cues from the apparent distinct effects on the activation phenotype in pDCs. While inhibition of cholesterol biosynthesis affects type I IFN induction, inhibition of cholesterol efflux does not (Saas et al. 2017). Nevertheless more clarity on the regulatory role of cholesterol metabolism in pDCs awaits further data.

3.7

The Elusive Role of IL-3 in pDC Immunobiology

In humans one of the mostly used cell surface markers for identifying pDCs is CD123 or IL-3 receptor alpha (IL-3Rα). Presence of these receptors on human pDCs has always led to speculations about IL-3 being a specific growth factor for pDCs. Early studies in the field suggested IL-3 to be a maturation-inducing cytokine for pDCs, driving tonsil-derived putative pDC precursors to IFN-producing mature cells (Grouard et al. 1997) and polarizing circulating pDC precursors into the putative type 2 dendritic cells (DC2) which could drive type 2 helper polarization in T cells (Rissoan et al. 1999; Kadowaki et al. 2000). It has also been reported that CD34+ human hematopoietic stem cells could be differentiated into pDCs through a collaborative action of IL-3, FLT3L, and thrombopoietin (Demoulin et al. 2012). Subsequently major confusion arose in the domain as murine pDCs do not express IL-3Rα (Swiecki and Colonna 2015) and the development of pDCs from the CDPs do not depend upon IL-3 signaling, at least in murine studies on pDC development (Reizis 2019). Thus the data on role of IL-3 on human pDCs and the fact that human pDCs uniformly express receptor for the cytokine, may point to potential for functional regulation in specific contexts. Such contexts may be associated with type 2 immune responses, characterized by cells that produce IL-3, viz. Th2 cells, mast cells, and basophils. On the other hand, in the systemic autoimmune disease SLE, wherein pDC-derived type I IFNs play major pathogenetic role (to be discussed in detail later in this volume), circulating IL-3 levels have been shown to be correlated with disease severity (Fishman et al. 1993; Gottschalk et al. 2015) and target gene transcript signature for IL-3 and type I IFNs shows a strong overlap in

3.8

Functional Heterogeneity of Plasmacytoid Dendritic Cells

39

SLE (Oon et al. 2019). Thus in humans a role of IL-3 signaling in defining functional identity of pDCs, if not even the developmental identity, cannot be ruled out. Notably, another recent study reports a putative role of IL-3 in tissue recruitment of pDCs in the context of infection. Severe pulmonary disease associated with SARS-CoV-2 infection is characterized by reduction in circulating pDCs (Severa et al. 2021). The study found that the circulating level of IL-3 is a dependable biomarker for disease severity, low levels being associated with severity (Bénard et al. 2021). The data suggested that IL-3 drives CXCL12 expression from lung epithelial cells which drive pDC recruitment, which operates in pulmonary viral infections but is deficient in some COVID-19 patients, contributing to disease progression.

3.8

Functional Heterogeneity of Plasmacytoid Dendritic Cells

While production of type I IFNs by pDCs in response to endosomal TLR activation is the most important functional attribute for these rare innate immune cells, heterogeneity of resting pDCs and functional diversification in response to the bona fide stimuli are of great interest too. PDCs exhibit discreet functional involvement in different clinical contexts, viz. type I IFN induction, antigen presentation as well as tolerogenic function by promoting T regulatory cell generation (to be discussed in subsequent chapters). Distinct subsets of pDCs specialized for each function is quite as possible as functional diversification of a homogeneous cell population in specific contexts. In humans a CD2high pDC subset has been shown to be different from a CD2low subset in terms of expression of lysozyme and cytotoxic activities, while both the subsets were found to be similar in terms of type I IFN induction in response to stimulation and expression of other cytotoxic molecules like granzyme-B or TRAIL (Matsui et al. 2009). Another study also described later a CD2highCD5+CD81+ human pDC subset, with more dendritic surface morphology is present in blood, bone marrow as well as tonsil. While they expressed the usual pDC surface markers and the TLRs, their transcriptional profile was found to be different with a low expression of IRF7 and they produced very little type I IFN in response to TLR9 activation (Zhang et al. 2017). A subset of CD5+CD81+ pDCs was also identified in mice with very similar deficiency in type I IFN induction. Human CD5+CD81+ pDCs were found to be rather strong inducers of T-cell proliferation, more efficient in Treg generation and also stimulated B-cell activation and promoted antibody production. Another study attributed the type I IFN inducing ability and the tolerogenicity to two discreet subsets of pDCs in mice, which can be distinguished by their surface expression of CD9 and variations in the expression of a pDC-specific cell surface molecule Siglec-H (Björck et al. 2011). A CD9+ Siglec-Hlow pDC subset was able to

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respond to TLR agonists by producing type I IFNs and expressed cytotoxic molecules. The CD9- Siglec-Hhigh population was deficient in IFN induction and was more efficient in driving Treg generation. In another study the Treg-priming activity was found to be restricted to a CD8α+ pDC subset in the context of experimental allergic asthma preclinical model in mice (Lombardi et al. 2012). On the other hand, CCR9 expression on pDCs has been linked to their tolerogenic function in gut, in the contexts of acute graft versus host disease (Hadeiba et al. 2008). Another more recent study reported that activation of human pDCs with influenza virus (known to activate TLR7 in pDCs) revealed a functional diversification by 24 h. Three functionally distinct pDC subsets were identified in the culture that could be differentiated based on the expression of the costimulatory molecules PDL1 and CD80 (Alculumbre et al. 2018). A PDL1+CD80- pDC subset maintained the type I IFN induction function, a PDL1-CD80+ subset assumed dendritic surface morphology efficiently presented antigens to T cells and the third PDL1+CD80+ pDC subset had both the type I IFN induction and antigen presentation functionalities. The subsets showed distinct transcriptional signatures and maintained their identity upon secondary stimulation. In autoimmune contexts, wherein type I IFN involvement in pathogenesis is established, viz. psoriasis and SLE, the PDL1+CD80- pDC subset was found to be more abundant. Finally, recent effort at single RNA sequencing on human pDCs revealed transcriptional heterogeneity at the baseline in vivo—a major dichotomy lying in terms of expression of the enzyme prostaglandin D synthase, while the bona fide pDC-specific genes like BDCA-2, BDCA4, E2-2 being homogeneously expressed (Ghanem et al. 2022). In the same study following influenza virus stimulation a wide diversity was apparent, with a rather minor population showing expression of the type I IFN transcripts. The transcripts that express surface molecules and were associated with the IFN-expressing pDCs were found to be LILRA5 and IL18RAP, which may be used as markers for IFN-producing cells in humans, provided further validation in a larger cohort of healthy individuals is done.

3.9

Regulators of Type I IFN Induction by pDCs

Type I IFNs are pleiotropic cytokines and thus can greatly modulate a number of immune cells participating in an immune response. The special ability of pDCs, to rapidly produce very high amounts of these cytokines in response to endosomal TLR activation by nucleic acid ligands of both pathogenic and self-origin, thus makes it imperative for rather tight control mechanisms to be put in place to prevent undesired aberrant activation. Accordingly a number of regulatory pathways are operative in pDCs which offer such control on pDC activation (Gilliet et al. 2008; Reizis 2019).

3.9

Regulators of Type I IFN Induction by pDCs

3.9.1

41

ILT7

A major family of pDC-intrinsic regulators are immunoreceptor tyrosine-based activation motif (ITAM)–bearing signaling receptors—ILT7 (Immunoglobulin-like transcript family 7) is one such regulatory receptor described in human pDCs (Rissoan et al. 2002; Cao et al. 2006; Cho et al. 2008). ILT7 contains four extracellular immunoglobulin-like domains and a cationic residue in the transmembrane region, which helps ILT7 to interact with other membrane-anchored adapter proteins. It was found that ILT7 forms a receptor complex with FcɛRIγ on the cell surface of human pDCs that transduces ITAM-mediated signaling. This signaling event leads to negative modulation of endosomal TLR-induced type I IFN production by human pDCs (Cao et al. 2006). To discover a physiologically relevant ligand for ILT7, a wide array of tumor cells and virus-infected cells, as they are expected to express a ligand for ILT7 thereby suppressing type I IFN induction, were screened on a GFP reporter cell line expressing GFP under the control of NFAT promoter and reporting activation of the ILT7- FcɛRIγ receptor complex (Cao et al. 2009). This screen discovered BST-2 (CD317) as cell–cell contact dependent ILT7 ligand, which is a glycoprotein originally described in bone marrow stromal cells, but later found to be expressed on plasma cells, multiple types of cancer cells as well as on a wide variety of cells in the body on exposure to IFN-α (Ohtomo et al. 1999; Walter-Yohrling et al. 2003; Blasius et al. 2006b). The BST-2-ILT7 interaction may play a critical role in case of cancer cells which have experienced and initial exposure to type I IFNs as part of the ensuing anticancer immune response, thereby upregulating BST-2 on them which then can downregulate further type I IFN induction by pDCs through ILT7. Of note here, it has been subsequently suggested that the regulatory mechanism involving BST-2ILT7 interaction may be restricted to circulating pDCs, while mature pDCs on TLR activation downregulate ILT7 expression and lose the regulation by BST-2. Interestingly, ILT7 crosslinking by antibodies on the mature pDCs does inhibit type I IFN induction (Tavano et al. 2013). In case of HIV infection it has been shown that Vpu, a viral protein, promotes BST-2-ILT7 interaction and thereby inhibit type I IFN induction by pDCs as an immune evasion mechanism (Bego et al. 2015).

3.9.2

BDCA2

Blood dendritic cell antigen 2 (or BDCA2, also known as CD313 and C-type lectin domain family 4, member C or CLEC4C) is a C-type lectin exclusively expressed on the surface of human pDCs, identified by using monoclonal antibodies that are specific for human pDCs (Dzionek et al. 2000). Soon after its discovery it was shown that monoclonal antibodies against BDCA-2 suppress type I IFN induction in pDCs in response to TLR activation (Dzionek et al. 2001; Fanning et al. 2006).

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Keeping aside the functional role of BDCA-2 in pDC biology, its pDC-specific expression has made it one of the most commonly used cell surface markers for pDCs in circulation and in different tissues, as well as for genetic targeting of pDCs in murine models (Dzionek et al. 2000; Boiocchi et al. 2013; Anderson et al. 2021). A mechanism dependent on intracellular calcium mobilization and proteintyrosine phosphorylation by src-family protein-tyrosine kinases was proposed for BDCA2 function. Intracellular calcium mobilization has been shown by other groups to be a key signaling event that control type I IFN induction in pDCs and pDC activation is restricted only within a window of physiologic calcium concentrations in the extracellular environment (Raychaudhuri et al. 2020). In later studies it has been shown that the inhibitory role on pDC activation in response to both BDCA-2 and ILT7 is mediated by a signalosome consisting of spleen tyrosine kinase (SYK), which associates with the ITAM motif in the transmembrane domain of these regulatory receptors of pDCs, and also involves tyrosine phosphorylation of BLNK and PLCγ2 (Röck et al. 2007; Aouar et al. 2016). The physiological ligand for this C type lectin receptor has been identified to be non-sialylated oligosaccharides with terminal galactose (asialo-galactosyl-oligosaccharides), which may be present on pathogens as well as infected host cells (Riboldi et al. 2011; Jégouzo et al. 2015). Interestingly, an envelope glycoprotein on the hepatitis C virus also engages BDCA-2, thereby inhibiting type I IFN induction by pDCs as an immune evasion mechanism (Florentin et al. 2012). Identifying other such ligands that may engage BDCA-2 in different patho-physiological contexts will allow appreciation of the biological functions of this receptor to a greater extent. Apart from the inhibition of type I IFN induction BDCA-2 engagement by antibodies have also been shown to inhibit TNF-related apoptosis-inducing ligand (TRAIL)-mediated cytotoxicity often exhibited by pDCs against virus-infected cells (Riboldi et al. 2009). The anti-BDCA-2 antibodies are internalized rapidly and are presented to T cells. This indicated that BDCA-2 may also play a role in ligand internalization and presentation (Dzionek et al. 2001).

3.9.3

Siglec-H

Sialic-acid-binding Ig-type lectin H (Siglec-H) is a cell surface protein with considerably restricted expression on mouse pDCs (Zhang et al. 2006) and functions as a negative regulator of type I IFN responses in response to TLR9 ligands (Blasius et al. 2006a; Takagi et al. 2011). Siglec-H is a murine CD33-family Siglec with two immunoglobulin domains, but lacking tyrosine kinase motifs in its cytoplasmic tail. Despite having structural features required for sialic acid binding there is not yet any evidence for definite endogenous ligand interaction with Siglec-H. The regulatory effects of this cell surface molecule in mouse pDCs are mostly demonstrated by specific antibody binding and in genetic deficiencies. Moreover, Siglec-H has been shown to be expressed also on specialized macrophages in mice, apart from in pDCs, and thus the data from genetic deficiencies of this gene may have influence of

3.10

Other Regulatory Surface Molecules in pDCs

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depletion of these macrophages as well (Swiecki et al. 2014). Another major question is the physiological relevance of Siglec-H related data in human immune system. Siglec-H is not in humans and the closest homologs are CD33 (a myeloid cell marker with minimal expression on pDCs), Siglec-9 (ubiquitous expression), Siglec-12 (ubiquitous expression), Siglec-P3 (expressed on human NK cells), and Siglec-7 (expressed in myeloid cells and NK cells in humans). As described the major inhibitory effect of Siglec-H in mouse pDCs seems to be on TLR9 activation leading to reduction in type I IFN induction. This regulatory modulation of pDCs were shown to be physiologically relevant as mice genetically deficient in Siglec-H was found to develop systemic lupiform inflammation and humoral autoreactivity on infection with the DNA-genome containing virus mCMV (Schmitt et al. 2016). This was presumably due to an increase in type I IFN induction in the absence of the regulatory control of Siglec-H (Takagi et al. 2011). Interestingly, in a recent study on infection with viruses with RNA genome, like LCMV or influenza virus, this finding was not recapitulated (Szumilas et al. 2021). There was no induction of systemic autoimmunity. This apparent discrepancy may be caused by a differential effect of Siglec-H-driven regulation on TLR9 versus TLR7 activation, which will be a very interesting revelation if reproduced and mechanistically understood. Although this may also result from usually short duration of infection by these viruses, which remains to be explored further. Another interesting data comes from differential effect of Siglec-H regulation on type I versus type III IFNs, later being much less affected in response to TLR9 activation! In addition to these differential effects of TLR activation and IFN induction, Siglec-Hdeficient pDCs show a reduced expression of CCR9, which may influence pDC migration in response to CCL25, the gut homing chemokine, especially in the context of induction of tolerance in the steady state (Hadeiba et al. 2008; Hoffman et al. 2021).

3.10

Other Regulatory Surface Molecules in pDCs

Several other surface receptors have been described in pDCs with potential for regulating their phenotype and activation profile in response to endosomal TLR stimulation. For example, CD300a, an inhibitory receptor expressed by many different immune cells, viz. NK cells, is also expressed on pDCs and CD300a triggering interestingly inhibits TNF-α production by human pDCs in response to TLR activation, while type I IFN induction remains unaffected, if not increased (Cantoni et al. 1999; Ju et al. 2008). Another receptor, NKp44, which is originally described in NK cells as an activatory receptor, is found to be expressed in human tonsillar pDCs and act as an inhibitory molecule by reducing type I IFN induction in response to TLR9 activation (Fuchs et al. 2005). LAIR-1, another receptor originally described in NK cells and known to be inhibitory to NK cells as well, have been shown to get expressed in human pDCs and regulate type I IFN induction. Interestingly, NKp44 and LAIR-1 expression is

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differentially regulated by IL-3 signaling, as it induces expression of NKp44 and inhibits expression of LAIR-1 on human pDCs (Bonaccorsi et al. 2010). It has been shown that the complement component C1q may act as a physio-pathological ligand for LAIR-1 and drive inhibition of pDC activation (Son et al. 2012). One of the C-type lectin receptors, Dendritic Cell Immunoreceptor or DCIR, is expressed on human pDCs. DCIR crosslinking by antibodies reduce type I IFN induction in response to TLR9 activation, on the other hand DCIR surface expression is also reduced concomitantly (Meyer-Wentrup et al. 2008). Of note, DCIR cross-linking does not affect costimulatory molecule expression by activated pDCs or antigen presentation. In fact antigens targeted to DCIR have been shown to be presented by pDC to T cells, thus offering a unique immunotherapeutic target (Meyer-Wentrup et al. 2008; Klechevsky et al. 2010). Two surface receptors that regulate pDC function as well as are markers of pDC activation, viz. PDC-TREM and Ly49Q, have been described in mouse pDCs, but not in humans. Among them, PDC-TREM has been shown to associate with another molecule Plexin-A1 on pDC surface and on receptor-ligand interaction between Plexin-A1 and Sema6D, the ligand for Plexin-A1, there is PDC-TREM signaling to activate Pi3K, leading to enhancement of TLR-driven type I IFN response (Watarai et al. 2008). The other one, Ly49Q was described to define two different mouse pDC subsets based on its expression and the Ly49Q+ mouse pDCs were more mature peripheral pDCs responding to synthetic as well as viral TLR ligands optimally (Kamogawa-Schifter et al. 2005). It has also been shown that type I IFNs reduce the expression of Ly49Q expression on pDCs in vitro and increase the frequency of Ly49Q- immature pDCs in the bone marrow, while MHC class I molecules can interact with Ly49Q on pDCs to drive maturation (Toma-Hirano et al. 2007; Tai et al. 2008). A ligand for Ly49Q, expressed by B cells has also shown to drive maturation of PDCs (Toma-Hirano et al. 2009). Ly49Q has also been shown to potentiate type I IFN induction by pDCs (Rahim et al. 2013). The immunoglobulin Fcγ receptor IIA or CD32 has been shown to play major role in pDC (both mouse and human) activation in physiological contexts of TLR ligand (e.g., DNA) containing immune complex driven TLR activation, presumably by driving efficient internalization of the complexes, and this pathway is found to be critical for type I IFN induction in autoimmune contexts like systemic lupus (Båve et al. 2003; Means et al. 2005). TLR9 ligands targeted to CD32 have been shown to induce higher type I IFN induction by pDCs as well (Tel et al. 2012; SepulvedaToepfer et al. 2019). Finally, CXCR4, the chemokine receptor regulating pDC development in the bone marrow niche and their emigration to periphery, has been shown recently to have a regulatory control over type I IFN induction in response to TLR activation as well. It has been shown that both in human pDCs as well as in mice a CXCR4 antagonist is able to inhibit type I IFN induction, which can also prevent a preclinical autoimmune disease in mice and provides new therapeutic targets for human autoimmune diseases with a pathogenetic role of pDC-derived type I IFNs, viz. systemic lupus (Smith et al. 2019).

3.11

3.11

Endocannabinoids and Cannabinoid Receptors

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Endocannabinoids and Cannabinoid Receptors

The endocannabinoid system consists of the endogenous cannabinoids (the endocannabinoids, which are bioactive lipid molecules), enzymes needed for endocannabinoid biosynthesis and degradation, and the receptors for which endocannabinoids act as agonists driving downstream signaling and thereby influencing cellular function (Lu and Mackie 2016; Rahaman and Ganguly 2021). The two major endocannabinoids are anandamide (or N-arachidonoylethanolamine or AEA) and 2-arachidonyl glycerol (2-AG) (Chiurchiù et al. 2015). The relevant enzymes that synthesize and degrade endocannabinoids regulate their physiological functions (Ramer et al. 2019), viz. fatty acid-amide hydrolase (FAAH), monoacylglycerol lipase (MAGL) and alpha/beta-hydrolase domain containing 6 or ABHD6 (Zurier and Burstein 2016; Rahaman and Ganguly 2021). Endocannabinoids play physiological roles in pain sensation, fear response and memory formation. Recent work has also implicated them as critical regulators of inflammation. Their roles in inflammation can be mediated by both neural regulations and receptor signaling in immune cells. The two established receptors for endocannabinoids, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) were originally discovered as receptors for the natural plant-derived cannabinoids, viz. Δ9-tetrahydrocannabinol or THC (Matsuda et al. 1990; Rahaman and Ganguly 2021). Role of the endocannabinoid system in DCs are rather newly revealed. PDCs express CB2 receptors. An inhibitory effect on type I IFN induction in pDCs in response to endosomal TLR activation was reported (Chiurchiù et al. 2013). This also points to the possibility of modulation of pDC function by natural and synthetic cannabinoids, although data are scarce for such experiments. More recently, ABHD6, an enzyme that degrades endocannabinoids, was shown to have enriched expression in human pDCs (Rahaman et al. 2019). ABHD6 is linked to systemic lupus erythematosus (SLE) by genetic association studies, a systemic autoimmunity with critical role of pDC-derived type I IFNs (Oparina et al. 2015; Lande et al. 2011; Sisirak et al. 2014; Ganguly 2018). A subset of SLE patients show higher expression of ABHD6 in PBMCs and well as purified pDCs, and this expression is correlated with ISG expression in the peripheral blood. Addition of the endocannabinoid 2-AG to healthy human pDC cultures did not affect type I IFN induction on TLR9 activation. But if ABHD6 is concomitantly inhibited using the inhibitor WWL-70, 2-AG inhibited type I IFN induction in pDCs in a CB2-dependent manner. This revealed a pDC-intrinsic regulatory function of endocannabinoid degradation by ABHD6, whereby the level of ABHD6 expression in pDCs is able to fine-tune a steady-state resistance mechanism driven by the endocannabinoid (Rahaman et al. 2019; Rahaman and Ganguly 2021). This newly revealed endocannabinoid-rheostat mechanism can play critical role in different patho-physiological contexts and warrants further exploration.

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3.12

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Metabolite Transporters and Receptors

In a recent study an oncometabolite, lactate released by cancer cells, was found to potently inhibit type I IFN induction by pDCs (Raychaudhuri et al. 2019). Human pDCs express the lactate receptor GPR81 as well as the lactate importers MCT1 and MCT2 (monocarboxylate transporters 1 and 2). It was found that the inhibitory function of cancer cell-derived lactate was mediated by both these cell surface proteins. Lactate engagement and resulting GPR81 signaling drives intracellular Ca2+ mobilization. On the other hand, intracellular import of lactate by the MCTs leads to a suppression of glycolysis, which is critical for pDC activation and type I IFN induction. Whether a similar regulatory mechanism driven by tissue lactate can regulate pDCs in other patho-physiological contexts, apart from cancer, remains to be explored. Type I IFN induction in pDCs in response to TLR stimulation is, as discussed earlier, critically linked to cellular metabolism, as evident from a glycolytic switch on TLR activation (Bajwa et al. 2016; Basit et al. 2018), inhibition of TLR activation in presence of lactic acid (Raychaudhuri et al. 2019) and indispensable involvement of mTORC1 in pDC activation (Cao et al. 2008). Interestingly, for its effects on cellular growth and cell division IL-3 is known to promote anabolic metabolism (Bauer et al. 2004; Lum et al. 2005). In fact, a recent study suggested a wider functional role of IL-3 in pDC biology, by driving expression of neutral amino acid transporters SLC7A5 and SLC3A2, critical for mTORC1 activation in response to TLR activation (Grzes et al. 2021). These amino acid transporters were also found to be expressed in pDCs infiltrating renal lesions in lupus nephritis. Thus whether IL-3 may play a role in metabolic reprogramming to influence pDC function, either uniformly or in specific clinical contexts, is of great interest.

3.13

Effect of Biological Sex on pDC Activation

An interesting aspect of pDC immunobiology is the documented evidence suggesting pDCs in males and females may respond to TLR activation differentially, a regulation which is rarely encountered in case of most other immune cells. As we will appreciate later in this volume type I IFNs released by pDCs play a major role in several autoimmune diseases, e.g. in systemic lupus erythematosus or SLE (Ganguly 2018). On the other hand, most of these autoimmune diseases, again we can take the example of SLE, are much more prevalent among females (Whitacre et al. 1999). Moreover, females are found to mount stronger immune response to viruses often not succumbing to severe disease outcomes, e.g. in case of HIV infection (Meier et al. 2009; Markle and Fish 2014; Guéry 2021). Thus the relationship between female biological sex and propensity for type I IFN induction from pDCs has been an intriguing domain of research (Guéry 2021).

3.14

Conclusions

47

It is well documented that human pDCs isolated from healthy female volunteers produce many fold more IFN-α in response to TLR7 activation (Berghöfer et al. 2006; Laffont et al. 2014). This difference is not considerable when pDCs are stimulated with TLR9 ligands. A role of the female sex hormones was contemplated upon though it was found in early studies that hormone receptor blocking could not interfere with this functional difference (Berghöfer et al. 2006). Nevertheless, subsequent studies did report that estrogen receptor signaling does contribute to this sex difference in pDC activation, probably for both TLR7 and TLR9 activation (Seillet et al. 2012; Laffont et al. 2014). In mice DC-specific genetic deficiency of estrogen receptor leads to abrogation of estrogen-driven potentiation of type I IFN induction from pDCs (Seillet et al. 2012). It has been shown that estrogen signaling in pDCs is associated with higher expression of the regulatory factor IRF5, which has been linked to higher type I IFN response in females (Griesbeck et al. 2015). On the other hand, it has been shown that the sex difference in type I IFN induction by pDCs do exist before puberty thus the biological sex itself, in addition to the sex hormones, play a role (Webb et al. 2019). In case of TLR7-driven type I IFN induction it has been shown that, apart from the effect of the female hormones, a critical role is played by the X chromosome dosage, assumed to be due to location of TLR7 gene in the X chromosome (Laffont et al. 2014). But the extra X chromosome in females are barred from gene expression by the mechanism of X chromosome inactivation (Augui et al. 2011). In the context of pDC activation too it was shown that TLR7 gene expression from both the X chromosomes may not be responsible for the sex-difference in type I IFN induction (Berghöfer et al. 2006). Interestingly, a polymorphism in TLR7 gene has been associated with a loss of the higher propensity for type I IFN induction in females, plausibly by affecting TLR7 protein expression (Azar et al. 2020). This polymorphism is as expected associated with higher viremia in females infected with HIV. In a recent study it was demonstrated that heterogeneity exists among human pDCs in terms of an escape of the TLR7 gene from the X chromosome inactivation mechanism, thus in some pDCs TLR7 gene dosage may become different due to this escape, thus affecting type I IFN induction (Hagen et al. 2020). This heterogeneity may explain the apparently incongruent reports of TLR7 gene dosage variations and intact X chromosome inactivation mechanism in the context of this sex-difference of pDC activation.

3.14

Conclusions

The major functional attribute of pDCs, i.e. type I IFN induction, is driven by the endosomal TLR7 and TLR9 molecules. The expression of the ligand-responsive TLRs in the endo-lysosomal compartments of pDCs is regulated and accomplished through a unique combination of intracellular trafficking and biochemical processing in pDCs. The ability of pDCs to respond to TLR activation by rapidly inducing type I IFNs in massive abundance is critically dependent on metabolic pathways, cellular

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respiration modalities as well as a plethora of molecular regulators. A functional heterogeneity within the apparently homogeneous pDC subset is also being appreciated with time. The tight regulation of type I IFN induction by pDCs is crucial for physiology and thus are offered by a number of cell surface receptors with inhibitory intracellular signaling as well as function of myriad transcriptional regulators.

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Chapter 4

Plasmacytoid Dendritic Cells and Infections

As we learnt from the sequence of discoveries that led to the discovery of plasmacytoid dendritic cells (pDCs), the major physiological function of these cells is assumed to be mounting a type I interferon (type I IFN) response on encountering viruses, as well as other pathogens like bacteria. This functional attribute of pDCs is powered by its specialized toll-like receptors (TLRs) that reside in the endo-lysosomal compartment and are able to recognize nucleic acid ligands. Thus the pivotal role of pDCs in infectious contexts remains type I IFN response and that in turn orchestrates both innate and adaptive and context-specific immunocellular responses. The chapter will progress shifting its focus across specific families of pathogenic microorganisms to chart the role of pDCs in these varied contexts of infection.

4.1

RNA Viruses and pDCs

TLR7 in the endosomal compartments of pDCs recognize RNA molecules and thus expected to play a critical role in immunity against RNA viruses (Heil et al. 2004). Most notable RNA viruses that are clinically relevant in humans are the orthomyxoviruses causing influenza, the picornaviruses causing common cold, polio, and hepatitis A (HAV), the flaviviruses causing hepatitis C virus (HCV), West Nile fever virus, Zika virus infection, yellow fever and dengue, the orthohepevirus causing hepatitis E (HEV), the rhabdovirus causing rabies, the filoviruses causing Ebola and Marburg hemorrhagic fever, the paramyxoviruses causing mumps and measles, coronaviruses causing common cold, SARS and in the recent pandemic COVID-19, respiratory syncytial virus (RSV) causing respiratory infections which is a orthopneumovirus, the arenavirus causing lymphocytic choriomeningitis (LCMV) and the retroviruses human T cell leukemia virus (HTLV) and human immunodeficiency virus (HIV) that cause T cell leukemia and AIDS, respectively. © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 D. Ganguly, Plasmacytoid Dendritic Cells, https://doi.org/10.1007/978-981-19-5595-2_4

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PDCs are able to mount a type I IFN response against most RNA viruses on receiving viral nucleic acids into the endosomal compartments harboring TLR7, independent of active infection of the pDCs by the viruses. Cellular infection by the viruses release their RNA genome into the cytosol which can be recognized by the RNA-helicase RIG-I, which also induces production of type I IFNs (Kato et al. 2006). Type I IFNs are induced in most virus-infected host cells as well as cDCs and macrophages through this cytosolic recognition. However, pDCs were shown to be more dependent on their endosomal TLR7 (Kato et al. 2005). In fact very few viruses infect pDCs despite their key role in immunity against viruses (Diebold et al. 2004; Crozat and Beutler 2004). Nevertheless, pDC infection by viruses have been shown in case of HIV, which is endocytosed followed by recognition of its genome by TLR7 (Beignon et al. 2005), as well as in case of RSV, which was shown to depend on the autophagy pathway to gain access to the endosomal compartment (Lee et al. 2007). In fact, UV-inactivated RSV incapable of infection fails to induce type I IFN response in pDCs (Hornung et al. 2004). Intriguingly, for a lot of RNA viruses (documented in DNA viruses too, as will be discussed in the next section) virus-infected cells rather than free viral particles are more potent inducers of type I IFNs in pDCs. It has been shown that HIV-infected CD4+ T cells are more potent activators of pDCs, which respond by producing type I IFNs through endosomal TLR activation, which in turn reduce viral replication in CD4+ T cells (Schmidt et al. 2005). In case of HCV, HTLV as well as yellow fever virus too infected cells were reported to induce type I IFN response in pDCs that depended on cell–cell contact, active viral replication, and TLR7 activation (Takahashi et al. 2010; Sinigaglia et al. 2018; Assil et al. 2019a). In case pDC activation in response to HCV-infected cells a mechanism involving exosomal transfer of viral RNA has also been demonstrated (Dreux et al. 2012). The same mechanism was also demonstrated by the same group in case of LCMV (Wieland et al. 2014). In a study with porcine reproductive and respiratory syndrome virus (PRRSV) it was found that while PRRSV induce a potent type I IFN response in vivo, it failed to do so in vitro in pDC cultures. Macrophages infected with PRRSV were able to activate pDCs, which not only involved exosome-mediated TLR-ligand transfer, was also dependent on close integrins-mediated and actindependent cell–cell contact between the macrophages and pDCs (García-Nicolás et al. 2016). In a more recent study it was demonstrated, using dengue, HCV, and zika virus, that the pDCs interact with virus-infected cells in a structured cell–cell junction, the so-called interferogenic synapse, which is supported by αLβ2 integrinICAM-1 interaction, recruits actin cytoskeletal network, and the endocytic machinery and allows viral RNA transfer (Assil et al. 2019b). Figure 4.1 depicts a model for formation of such interferogenic synapses involving pDCs. Apart from recognizing virus-infected cells and transferring in activating ligands from them these synapses may also serve the pDCs to seclude the type I IFN response locally, thus avoiding wider inflammation. To what extent anti-virus immunity in vivo is dependent on formation of these “interferogenic synapses” for effective viral clearance and prevention of systemic inflammation, warrants further exploration.

4.2

Human Immunodeficiency Virus and pDCs

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Fig. 4.1 A model depicting interferogenic synapse formed between virus infected host cells and plasmacytoid dendritic cells. Plasmacytoid dendritic cells get close to virus-infected host cells and form an integrin-dependent junctional space supported by cytoskeletal scaffold, the so-called interferogenic synapse, which serves to viral sensing by toll-like receptors as well as localized type I interferon response. (Reproduced with permission from Assil S et al., 2019b)

4.2

Human Immunodeficiency Virus and pDCs

Role of pDCs in human immunodeficiency virus (HIV) infections, perhaps the most clinically relevant retrovirus, is of great interest. Apart from the great public health problem HIV infection pertains to, by causing acquired immunodeficiency syndrome (AIDS), major reason of this interest lies in the fact that human pDCs is known to express CD4 molecule, which is the receptor for HIV, along with CCR5 and CXCR4, which are coreceptors for HIV infection. Thus, just like the CD4+ T cells, HIV has the ability to infect pDCs as well. PDCs from circulating blood in patients acutely infected with HIV do show HIV-1 proviral DNA and pDC frequency reduces in blood (Schmidt et al. 2004). Healthy pDCs

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have also been shown to get infected with HIV, to show cytopathic effects forming multinucleated syncytia. PDCs can get infected by either free viral particles or through CD4+ T cells infected with HIV (Iwasaki 2012; Fig. 4.2). Similar finding was also registered in humanized mice infected with HIV as well as in HIV patients, showing similar reduction of circulating pDCs and CD4+ T cells (Soumelis et al. 2001; Killian et al. 2006; Zhang et al. 2011). Nevertheless, HIV replication within pDCs is restricted and non-productive infection can activate endosomal TLR7 and induce type I IFN production (Beignon et al. 2005). In fact, antibodies to IFN-α has a permissive effect on HIV infection of pDCs, pointing to role of induction of type I IFNs in preventing productive infection by the virus (Schmidt et al. 2004). PDC activation by HIV seems to be dependent on virus entry, as blocking CD4 using an antibody or inhibiting endocytosis abrogates pDC activation in response HIV (Reszka-Blanco et al. 2015; O’Brien et al. 2016). In acute HIV infection there is evidence of induction of type I IFNs by pDCs in the lymph nodes (Lehmann et al. 2010). Interestingly, in humanized mice infected with HIV-1 it has been found that extent of pDC activation and immune activation in the lymph nodes is rather associated with CD4+ T cell depletion (Zhang et al. 2011). Similar indications come from patients as well, especially from the finding that women, who mount a far higher type I IFN response from pDCs compared to men, are actually rapid progressors to AIDS due to T cell depletion, despite having lower viral loads early on (Meier et al. 2009). This enigmatic phenomenon has also been explored in humanized mouse model of the infection, wherein depletion of pDCs using a monoclonal antibody targeting BDCA2 leads to lower induction of type I IFNs, higher viral load but also decelerated CD4+ T cell depletion (Li et al. 2014; Zhao et al. 2018). In the chronic phase of the infection pDCs have been shown to be persistently activated producing type I IFNs, again activated pDCs actually associate with disease progression (Sabado et al. 2010; Miller and Bhardwaj 2013). In humanized mice too depletion of pDCs or systemic blockade of type I IFN receptor in the chronic phase of the disease led to higher viral load but improved immune functions (Li et al. 2014; Zhang et al. 2015). Further support for this comes from the report that HIV patients with high viral load but less severe disease actually show a lower ISG expression in their peripheral blood (Rotger et al. 2011). Thus the role of pDCs in HIV infection, in both the acute and chronic phases, seems to accelerate immunodeficiency, presumably by aggravating inflammation in lymphoid organs by induction of type I IFNs, thereby promoting recruitment of T cells, which succumbs to the virus. In fact, in humanized mice anti-retroviral therapy has been shown to be more efficacious in preventing immunodeficiency with concomitant systemic blockade of type I IFN receptors (Cheng et al. 2017). Thus depleting pDCs or blocking type I IFN response may actually be a beneficial therapeutic strategy for the immunodeficiency disease.

4.2

Human Immunodeficiency Virus and pDCs

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Fig. 4.2 Modes of recognition of human immunodeficiency virus by plasmacytoid dendritic cells. Cell free human immunodeficiency virus (HIV) can infect plasmacytoid dendritic cells and gets internalized by endocytic machinery, reaches endo-lysosomal compartments driving recognition of the RNA genome by TLR7. On the other hand, CD4+ T cells infected with HIV can make close junctional space with pDCs supported by cytoskeletal scaffold and thereby releasing viral particles in the cytosol. Then either the viral genome gets access to the endo-lysosomal compartment to be recognized by TLR7 or viral replication may also happen. (Reproduced with permission from Iwasaki A, 2012)

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PDCs and the Novel Coronavirus SARS-CoV-2

A major characteristic of immune response in the context of SARS-CoV-2 novel coronavirus infections (coronavirus diseases of 2019 or COVID-19) has been a marked depletion in circulating pDCs in the patients, more so in the ones suffering from severe respiratory disease (Yoshida et al. 2022). Severity in COVID-19 is established to be driven by a systemic hyperinflammation. How depletion of circulating pDCs is linked to the hyperinflammatory mechanisms is far from clear. It has been suggested that human pDCs respond to SARS-CoV-2 by TLR-driven type I IFN induction, which is independent of ACE-2 but depends on BDCA4 (Neuropilin1) on pDC cell surface (Severa et al. 2021). But in severe COVID-19 patients the systemic pDC depletion and inefficient type I IFN induction remain elusive. An interesting report described ability of pDCs to sense SARS-CoV-2 envelop protein through TLR2, in addition to the usual sensing of viral nucleic acids by endosomal TLR7 (van der Sluis et al. 2022). TLR7 activation triggers type I IFN induction as expected, while TLR2 activation drives NFκB activation and induction of IL-6. On the other hand, recognition of SARS-CoV-2 spike protein by the pDC surface molecule neuropilin-1 (BDCA4) triggers an inhibitory signal for IRF7 translocation and type I IFN induction. This may at least partially explain reduction in type I IFN response in response to the virus. Whether the same differential pathway engagement also drives pDC apoptosis leading to lower peripheral abundance is not clear and remains to be explored. As described earlier, a role of IL-3 has also been implicated in pDC dysfunction in SARS-CoV-2 infection, leading to deficient pulmonary recruitment of pDCs and deficient type I IFN response in situ (Bénard et al. 2021).

4.4

DNA Viruses and pDCs

Most notable DNA viruses that cause human diseases are the herpesviruses HSV-1, HSV-2, varicella-zoster virus (VZV) causing chicken pox and human cytomegalovirus (CMV), the hepadnavirus causing hepatitis B (HBV), the adenoviruses causing common cold and meningitis and the papillomaviruses causing genital warts and cervical cancer (HPV). PDCs are expected, and documented for some clinically relevant viruses, to respond to DNA viruses by recognizing the unmethylated CpG motifs in the DNA genomes by their endosomal TLR9 receptors and drive a type I IFN response. PDC-derived type I IFNs are critical mediators in protective immune response against herpesviruses, e.g. HSV-1, HSV-2, Varicella-zoster virus, human cytomegalovirus (Baranek et al. 2009; Swiecki et al. 2013). Viral DNA recognition by TLR9 in pDCs leading to fast and copious type I IFN induction drive the subsequent innate and adaptive immune activation against these viruses (Baranek et al. 2009). Mouse cytomegalovirus (MCMV) infection has been a standard preclinical model for

4.4

DNA Viruses and pDCs

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elucidating protective immunity against such viruses. PDCs isolated from the infected animals produce type I IFNs ex vivo without any restimulation (Dalod et al. 2003). On the other hand, in vivo depletion of pDCs using monoclonal antibodies against BST-2 abrogates the systemic type I IFN induction and prevents anti-viral NK cell function (Krug et al. 2004). PDC deficiency affected by genetic deficiency of IKAROS, a critical transcription factor for pDC development and maturation, also leads to absent type I IFN response to MCMV (Allman et al. 2006). Interestingly, an inducible genetic deficiency model, in the BDCA-2-DTR mice, where injection of diphtheria toxin kills all pDCs as they express the receptor for the toxin, showed that the non-redundant role of pDCs may be restricted only to systemic infection by HSV-1, leading to deficient type I IFN induction and CD8 activation. More local infections like, in vaginal infection model, absence of pDCs were found not to affect the immune response and outcomes (Swiecki et al. 2013). Alphaherpesviruses are known to generate two distinct types of viral particles in vivo, the heavy or H particles which is the whole infectious virion, and the light or L particles which are devoid of the mature nucleocapsid (Heilingloh and Krawczyk 2017). Biological role of these L particles is far from clear—suggestions have been made that they function as immune decoys to seclude antibodies, to inhibit the protective immune response, or to prime uninfected host cells (Dargan and SubakSharpe 1997; Birzer et al. 2020; Delva et al. 2021). L particles produced by HSV-1infected human MoDCs in vitro render uninfected MoDCs deficient in CD83 and IL-6 receptor expression (Heilingloh et al. 2015; Birzer et al. 2020). Recently it has been reported that during alphaherpesvirus infection the L particles can also modulate porcine pDC function through a hitherto unknown mechanism. L particles were found to abrogate the type I IFN induction by pDCs in response to the H particles. The type I IFN induction by the H particles as well as the inhibition mediated by the L particles were shown to be mechanistically linked to specific surface glycoproteins and nature of their glycosylation on these viral particles (Delva et al. 2021). A similar modulatory role of L particles on type I IFN induction, in response to HSV-1 infection in human PBMCs, was also reported. This offers a window into a hitherto unappreciated molecular regulatory module for type I IFN induction by pDCs in response to viral infections, or possibly even in other contexts of endosomal TLR stimulation, which warrants further exploration in deeper detail. HPV viral-like particles, not having its DNA genome, has been shown to get internalized and potentiate CpG-driven type I IFN induction in pDCs in vitro and pDCs do get recruited in cervical cancers with documented HPV infection (Lenz et al. 2005; Bontkes et al. 2005). While data on pDC activation in response to intact HPV viral particles are scanty, in the relevant tissues of infected individuals, both in skin warts as well as in cervical cancers, pDC abundance, and in situ type I IFN induction are noted by different studies (Bontkes et al. 2005; Saadeh et al. 2017). However, in pDCs recruited in the cervical cancers have been shown to be dysfunctional and tolerogenic, presumably due to factors in tumor microenvironment (Demoulin et al. 2015). Interestingly, in non-small cell lung cancers it has been shown recently that concomitant HPV infection prevents intra-tumoral dysfunction of pDCs (Koucký et al. 2021).

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These data showing viruses rich in ligands with potential for activating TLR9 in pDCs are in fact protected from pDC function in tissue contexts and rather may drive pDC dysfunction is also recapitulated in HBV infections. The number of circulating pDCs decrease in active HBV infection (Duan et al. 2004) and they induce differentiation of T regulatory cells more compared to healthy pDCs (Hong and Gong 2008). HBV viral particles fail to activate pDCs and HBsAg, the S antigen on HBV, inhibits TLR9 activation and type I IFN induction in pDCs (Xu et al. 2009; Woltman et al. 2011). In chronic HBV infection circulating pDCs were reported to be dysfunctional which was linked to a reduced expression of OX40L on them (Martinet et al. 2012). As we discussed with RNA viruses, whether free viral particles or the virusinfected host cells are more potent in activating pDCs in the physio-pathological contexts is a domain of active research (Webster et al. 2016). One may consider that infected cells are more potent in driving pDC activation in vivo with DNA viruses as well. In fact, in a recent study with CMV it was reported that human pDCs respond with a TLR9-dependent type I IFN response to CMV-infected fibroblasts, but not to free CMV. This involved integrins mediating cell–cell adhesion and transfer of virions to pDCs (Yun et al. 2021). If these data are generalizable, then the affected tissue microenvironment as well as virus-derived immunomodulators may ultimately determine whether pDC activation and type I IFN induction is encountered in a specific context of viral infection and whether that can effectively drive anti-viral immunity.

4.5

PDCs in Bacterial Infections

Major focus on the role of pDCs in the context of infections has been on viruses, variably due to the characteristic nucleic acid ligands available in viral genome, their ability to infect host cells and in the process of replicative proliferation release of nucleic acids, as well as due to the ability of some viruses to infect pDCs and thus activate them directly. Moreover, type I IFNs, for which pDCs are the major and most efficient cellular sources in the body, are long since been identified to be critical regulator of anti-viral immune response. On the other hand, in case of bacterial infections, pDCs, having poor phagocytic ability, mostly need to engage with other immune cells to sense the relevant bacterial ligands and get activated. But bacterial genome is rich in unmethylated CpG motifs, the bona fide ligands for TLR9 in pDCs, thus should be great inducer of type I IFN response. Type I IFNs are very efficient in orchestrating cytotoxic responses against infected host cells and thus were mostly explored in the context of intracellular bacteria (Bekeredjian-Ding et al. 2014; Bogdan et al. 2004). Nevertheless, role of type I IFNs in immunity against bacteria is indubitably essential (Mancuso et al. 2007; Kelly-Scumpia et al. 2010). But role of pDCs as an essential source of the type I IFNs in specific contexts of bacterial infections is not yet fully established.

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PDCs in Bacterial Infections

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69

Extracellular Bacteria and pDCs

Among the extracellular bacteria some effort has been put to explore the role of pDCs and pDC-derived type I IFNs in the context of the gram-positive bacteria Staphylococcus aureus, the major pathogen for wound, other tissue infections, and the gram-negative bacteria causing gut infections. Initial cues came much before pDCs were discovered when it was found that the cells producing IFN-α in response to dead bacteria (S. aureus) were non-lymphocytic cells with ability to activate NK cells, thus they presumably were the pDCs (Rönnblom et al. 1983). This was also supported by a later report showing a CD3-CD14-CD19-HLA-DR+CD4+ cell in human PBMC culture, again matching with the established description of human pDCs, produced copius IFN-α in response to S. aureus and E. coli (Svensson et al. 1996). In an interesting study it was shown that live S. aureus could induce IFN-α production in purified human pDCs only with autologous serum and it was independent of TLR2, dependent on endosomal TLRs in pDCs and the Fc receptor CD32 on pDCs (Parcina et al. 2008). These data point out that response to these bacteria by pDCs may be by uptaking antibody-bound cells and thus part of a memory response against the bacteria. Moreover, in a humanized mouse model it was demonstrated that in response S. aureus pDCs got activated through TLR9 and drove B cells to produce IgG4 antibodies as well as IL-10 (Parcina et al. 2013). A recent study also implicated activation of TLR1 and TLR2, TLRs not usually associated with major role in pDCs, for human pDC activation in response to extracellular gram-positive bacteria (Raieli et al. 2019). Another study confirmed that human pDCs do get activated in response diverse extracellular bacteria, viz. Neisseria meningitides, Hemophilus influenzae, and S. aureus, leading to production of IFN-α, TNF-α, and IL-6 as well as expression of co-stimulatory molecules like CD80. The study also confirmed that human pDCs were able to internalize S. aureus cocci (Michea et al. 2013). Bacteria like H. influenza and S. aureus may first encounter pDCs in the oro-pharyngeal mucosa and tonsillar epithelium and antigen presentation to T cells may play an important role in immunity against these infections. Of note here, a cysteine protease produced and released by S. aureus, Staphopain B, has been shown to cleave the non-chemokinetic chemerin precursor to the active chemokine (Kulig et al. 2007). Chemerin is a potent chemokine for pDCs and has been demonstrated to function in different clinical contexts to recruit pDCs in the site of inflammation, as pDCs express the cognate receptor CMKLR1 (Albanesi et al. 2010; Ghosh et al. 2016; van der Vorst et al. 2019). Thus chemerin activated by S. aureus may play a major role in recruiting pDCs in the S. aureus infected tissues. Interestingly, a number of other extracellular bacteria do not seem to activate pDCs to produce type I IFN, viz. coagulase positive Staphylococcus or Streptococcus pyogenes (Veckman and Julkunen 2008; Bekeredjian-Ding et al. 2014), perhaps pointing to crucial contributions from prior exposure, cognate antibody response and context-specific chemotactic cues, although further studies will be essential to understand this in greater detail.

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The gram-negative bacteria of Chlamydia sp., C. pneumonia causing lung infections and Chlamydia trachomatis causing genitor-urinary and ophthalmic disease (one most common infectious causes of blindness), have been shown to recruit both cDCs and pDCs in the infected tissue (Agrawal et al. 2009; Crother et al. 2012). PDC depletion using monoclonal antibody or BDCA2-DTR transgene in an acute C. pneumoniae infection model in mice led to delay in immunocellular recruitment and significant reduction in cytokine production in situ, which in turn lead to impaired bacterial clearance resulting in a severe chronic inflammation (Crother et al. 2012). On the other hand, increasing pulmonary pDC abundance by FLT3L treatment resulted in more severe acute lung inflammation. In another study too pDC depletion in this context was associated with more pro-inflammatory cytokine production by T cells and reduction in Treg cells in the lungs, thus fueling the tissue inflammation (Joyee and Yang 2013). A role of pDCs in regulating Treg abundance in the lungs in the context of a bacterial pneumonia was also reported with Klebsiella pneumonia infection model in mice, wherein BDCA2-DTR transgene mediated systemic pDC ablation was associated with increased pulmonary Tregs and delayed clinical recovery (Lippitsch et al. 2019). In case of C. trachomatis infection of the cervix pDC infiltration in the tissue was more with patients having more severe cervical inflammation and on therapy pDC numbers were reduced faster than cDCs (Agrawal et al. 2009). Infection by another extracellular bacteria, Bordetella pertussis that infect the lungs causing whooping cough or pertussis, have also been documented in preclinical model to be associated with tissue recruitment of pDCs as well as type I IFN induction in situ (Wu et al. 2016). Of note, in this case the type I IFN derived from pDCs was linked to a delayed Th17 response in the lungs and blocking type I IFN induction led to early Th17 cell abundance and more severe inflammation. In case of the gut pathogen Citrobacter rodentium, a murine strain mimicking E. coli infection in humans, pDC depletion again leads to more severe colonic inflammation (Toivonen et al. 2016; Rahman et al. 2019; Pöysti et al. 2021). Thus a major role of pDCs in contexts of infection with extracellular bacteria seems to be modulating the course of the disease by regulation of local inflammation.

4.5.2

Intracellular Bacteria and pDCs

Listeria monocytogenes is an intracellular bacterium that infects humans, especially pregnant women, children, old individuals, and the immunosuppressed patients, through contaminated food and it can cross placenta and infect the fetus. L. monocytogenes microbiology and the immune response against this bacterium have been considerably explored and these studies also provide useful general insights for intracellular bacterial pathogenesis and immune response (Radoshevich and Cossart 2018). Interestingly, a comprehensive study on L. monocytogenes infection in mice demonstrated that while type I IFNs are produced and are critical cytokines in the immune response against these bacteria, the induction was neither

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dependent on TLR9 or pDCs (Reutterer et al. 2008; Stockinger et al. 2009). Another family of clinically relevant intracellular bacteria, Burkholderia mallei and Burkholderia pseudomallei, causing the disease melioidosis in humans, has been shown to get internalized by pDCs and drive type I IFN response as well as intracellular bacterial killing in both human and mice (Williams et al. 2015). Moreover, mice (BALB/c) more susceptible to the infection has been found to have pro-pathogen pDCs (more type I IFN induction and less intracellular killing) as compared to mice (C57BL/6) that are able to protect themselves from the infection, pointing to plausible role of pDCs in the immune response and inflammatory aftermaths in Burkholderia infection. But data in this infection is rather scanty and need further explorations. It is not yet explored to a great extent if pDCs and pDC-derived type I IFNs play any critical role in tuberculosis (TB), caused by perhaps the most elusive and troublesome intracellular bacteria for humans, mycobacterium, which primarily infect macrophages. TB is spread when patients expel the bacteria into the air (e.g., in droplets released during coughing). While the infection typically affects the lungs (called pulmonary TB), it can spread to many other body sites and cause local granulomas or systemic diseases (extrapulmonary TB that may affect lymph nodes, bones, gut, CNS and many other tissues). Adult males seem to be affected more often. Infection does not always cause clinically apparent disease—the so-called latent TB. Close to one fourth of World’s population is infected by the bacteria as per 2021 report from World Health Organization. Although induction of type I IFNs in response to mycobacteria infection in DCs had been reported (Remoli et al. 2002). Absolute numbers of both cDCs and pDCs in circulation have been shown to be reduced in TB patients (Lichtner et al. 2006; Lu et al. 2017; Dirix et al. 2018). Moreover, pDCs from active TB patients have been shown to be functionally impaired in terms inducing type I IFN in response to a DNA virus ex vivo (Lichtner et al. 2006). Thus pDCs may be a critical cellular target in tuberculosis among the diverse immune evasion mechanisms deployed by mycobacteria. Interestingly, pDCs infiltrate the local skin after intradermal injection of tuberculin, for testing reactivity against TB signifying past exposure, and produce type I IFNs in situ. Although this has been linked to local expression of the antimicrobial peptide LL-37 and TLR9 activation in pDCs by LL37-DNA complexes formed in situ (Bond et al. 2012), which is documented to be a critical pathogenetic event in several contexts of autoreactive inflammation (to be discussed in a later chapter). Moreover, while exploring immunocellular crosstalk between cDCs and pDCs in response to bacille Calmette-Guérin (BCG), the mycobacterial strain used in the mostly used pediatric vaccine against TB in the endemic areas, it was found that pDCs were not infected by BCG but responded to BCG-infected cDCs by upregulating costimulatory molecules and the cytotoxic molecule granzyme B, without any type I IFN induction. On the other hand the presence of pDCs in co-culture enhanced cDC activation and killing of phagocytosed bacteria (Lozza et al. 2014). Thus for mounting an immune response against this vaccine strain of mycobacteria pDCs seem to play an important role and this also supports the

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possibility of immune evasion by the bacteria driving pDC dysfunction, as encountered in patients with active TB. Further studies in this domain are thus warranted to provide interesting insights for immunopathogenesis of tuberculosis as well as potential therapeutic targets.

4.6

PDCs in Malaria

Infection of plasmodium parasites, transmitted through bites of infected female Anopheles mosquitoes, causes acute febrile illness, at times complicated by systemic inflammation and severe disease, in malaria. Among the five humanized plasmodium species two poses greatest threat—P. falciparum and P. vivax. Infection with P. falciparum can cause a central nervous system inflammation with very high mortality (cerebral malaria), while infection with P. vivax usually causes a benign form of the disease. As per data in 2020 presented by World Health Organization more than 240 million infections and more than 600,000 deaths were documented in the year 2020 itself. Research into the pathogenesis of malaria involve both the humanized species as well as rodent species like P. yoelii and P. chaubaudi (causing benign malaria in mice), P. berghei (mimicking cerebral malaria in mice). On mosquito bite or artificial inoculation in model animals, sporozoite forms of the parasite enter the bloodstream, reach the liver, infect hepatocytes and further differentiate, forming the pre-erythrocytic stage. In a week or so, hepatocytes rupture, releasing thousands of merozoite form of the parasite back into blood where they infect the erythrocytes (red blood cells or RBCs). In RBCs the merozoites mature through the stages of initial ring forms and trophozoites to mature schizonts over a period of 2–3 days. Then schizonts rupture releasing more merozoites back into the blood and they infect new RBC, in a new cycle. This is called the erythrocytic or blood-stage of infection. As the RBCs rupture and release merozoites into the circulation the acute febrile symptoms are manifested. In a severe disease excessive RBC destruction lead to anemia, systemic inflammation, and microvascular accumulation of infected RBCs (iRBCs) leading to tissue damage. Naturally acquired immunity to the pre-erythrocytic stages is minimal, leading to recurrent infections in endemic areas. But humoral immune response does ensue against sporozoites that at times prevent hepatic infection or drive killing of infected hepatocytes by antibody-dependent cytotoxicity, as well as by IFN-γ-producing CD4+ and CD8+ T cells, γδ T cells, and NK cells. On the other hand, the erythrocytic stage drives an intense inflammation and cytokine response (IL-1β, IL-6, IFN-γ, TNF-α, and IL-12) with macrophage activation which phagocytose iRBCs, which is also aided by an antibody response. Regulation of inflammation is critical once parasitemia is under control and failure to do that leads to severe disease. CD8+ T cells and NK cells are critical players in immunity against malaria (Good and Doolan 1999; Tsuji and Zavala 2003). Given the potent influence of type I IFNs on CD8+ T cells and NK cells, a key role for pDCs is also expected, though much

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less explored. A role of pDCs in the immune response against plasmodium was also suggested by the finding that schizonts are capable of activating endosomal TLRs in pDCs and inducing type I IFN response (Pichyangkul et al. 2004; Gazzinelli et al. 2014). Intact schizonts and schizont-extracts upregulate costimulatory molecules on pDCs and drive TLR9 activation, plausibly driven by unmethylated CpG motifs in the parasite genome. It has been suggested that hemozoin, the insoluble crystal formed in the food vacuoles of plasmodium, may bind parasite DNA and transport it into the endosomal compartments of pDCs to activate TLR9 (Parroche et al. 2007). In the experimental cerebral malaria induced by P. berghei ANKA it has been shown that inhibition of TLR9 in vivo using E6446, a synthetic antagonist for endosomal TLRs, led to reduced cytokine response as well as the severe signs of CNS inflammation, like limb paralysis, brain vascular leak, and death (Franklin et al. 2011). In the same model of cerebral malaria it has also been shown that genetic deficiencies of IRF7 and IFNAR1 protect mice (Sharma et al. 2011). Nevertheless, potential for AT rich loop motifs of parasite DNA to activate the cytosolic DNA sensors have also been reported, which can lead to type I IFN induction from other innate immune cells as well. Moreover, genetic deficiency of TLR7 protected P. berghei-infected mice from cerebral malaria and death, pointing to a critical role of TLR7 activation too in the inflammatory aftermaths of infection (Baccarella et al. 2014). In patients infection with P. vivax there is a reduction in circulating pDCs that may be due to tissue recruitment (Jangpatarapongsa et al. 2008). Interestingly, a recent study reports that in P. falciparum infection there is an increase in circulating FLT3L, the key growth factor for DC subsets, but there was a reduction in the circulating cDCs and pDCs (Loughland et al. 2021), which points to an interesting immune regulation that warrants exploration. In a preclinical study with P. chaubaudi infection in mice, which largely mimics the benign malaria caused by P. vivax in humans, it was shown that TLR9 activation in pDCs leading to type I IFN induction was redundant for immune response against the parasite. The course of P. chaubaudi infection in mice was not affected by TLR9-deficiency. IFNARdeficient mice are also able to control infection as are mice depleted of pDCs using a monoclonal antibody (Voisine et al. 2010). Interestingly, another study reported a non-redundant role of TLR7 activation with the same preclinical model as well as with other parasite species (Baccarella et al. 2013). In a more recent study on another preclinical model in mice using P. yoelii pDCs were found to be the major producer of type I IFNs on infection. Type I IFN induction in pDCs was upon TLR7 activation but was also dependent on interaction with CD169+ macrophages. The macrophages activation was in turn dependent on activation of the cytosolic DNA sensor STING by parasite-derived ligands (Spaulding et al. 2016). The study also reported that type I IFNs were key contributors to inflammation in response to the infection, as IFNAR-deficient mice showed much less inflammation and better survival post-infection. PDC activation was also documented in children suffering from severe malaria. Taken together, it seems that pDCs and type I IFNs are major contributors to the debilitating inflammation in severe disease following plasmodium infection and thus may offer interesting therapeutic targets. But further exploration is warranted in this context.

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PDCs in Fungal Infections

Contemplation on a role of pDCs in anti-fungal immunity perhaps started with a study that showed that a thymus-derived peptide, thymosin alpha 1, activate human cDCs and pDCs, in terms of promoting their phagocytic capacity and IL-10 production in response to Aspergillus fumigatus (Romani et al. 2004). Moreover, Ammophilus fumigatus DNA, with plenty of unmethylated CpG motifs, is known to trigger TLR9 in both mouse and human pDCs and induce cytokine production (Perruccio et al. 2004; Ramirez-Ortiz et al. 2008). Mannoproteins from Cryptococcus neoformans synergize with CpG-DNA to drive potent activation of pDCs in terms of cytokine induction, implying an adjuvant action of these fungal mannoproteins for TLR9 activation in pDCs, plausibly mediated through specific C-type lectin receptors on pDC surface (Dan et al. 2008). Among the receptors known in fungal recognition that are expressed by pDCs, dectin-1, dectin-2 and mannose receptor have been documented in both mice and human (Milone and Fitzgerald-Bocarsly 1998; Gavino et al. 2005; Seeds et al. 2009; Joo et al. 2015). As a more direct evidence for pDC involvement in anti-fungal immune response comes from the data that human pDCs can directly respond to A. fumigatus hyphae in vitro, though in albeit higher pDC-fungus ratio, spread out over the hyphal surface, produce IFN-α and TNF-α and inhibited hyphal viability to a great extent (Ramirez-Ortiz et al. 2011). There was also evidence for a lot of pDCs dying in this setting, presumably in response to the fungus-derived gliotoxin. Interestingly, pDC lysates also showed anti-fungal activity, which was shown to be due to calprotectin, a known anti-fungal host molecule, released from the dying pDCs. There is even suggestion of formation of DNA extracellular traps by pDCs, quite similar to similar phenomenon observed in neutrophils, wherein calprotectin is an active molecule present on the DNA traps (Urban et al. 2009; Loures et al. 2015). But this phenomenon in pDCs needs deeper exploration to consider it as a generalized response for pDCs. Supporting the role pDCs in immune response in aspergillosis it was shown that mice deficient in either pDCs (in the context of antibody-mediated depletion of pDCs) or IFNAR1 (genetic deficiency) were much more susceptible to the infection (Ramirez-Ortiz et al. 2011). In case of C. neoformans also it was shown that both murine and human pDCs do phagocytose the yeast cells and inhibit C. neoformans growth plausibly by generating reactive oxygen species (Hole et al. 2016). Neutralization of dectin-3 on human pDCs was shown to inhibit pDC response to C. neoformans and pDCs from dectin-3 knockout mice showed reduced phagocytosis and growth inhibition of the fungus, while deficiency of dectin-1, dectin-2, and MR showed less marked reduction in pDC response to the fungus. Thus pDCs may use combination of different receptors, in a context-specific way, to recognize and respond to different fungi.

References

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Conclusions

PDCs were originally identified as the most efficient producers of type I IFNs in the context of viral infections. But pDCs do play crucial roles in infections caused by bacteria, parasites as well as fungi. However, the role of pDCs, offered through both its IFN induction and antigen presentation functions, have now been realized as being more diverse depending on the specific infectious contexts. The intricate regulation and diverse functional outcomes are not only valid with respect to different groups of pathogenic microorganisms. Even for specific infections the role of pDCs evolve through stages of infections and with respect to the cellular crosstalk within different immune cell subsets.

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infection involves pathogen-sensing and inflammatory pathways distinct from conventional dendritic cells. J Immunol 196(11):4750–4759. https://doi.org/10.4049/jimmunol.1600235 Tsuji M, Zavala F (2003) T cells as mediators of protective immunity against liver stages of Plasmodium. Trends Parasitol 19(2):88–93. https://doi.org/10.1016/s1471-4922(02)00053-3 Urban CF, Ermert D, Schmid M, Abu-Abed U, Goosmann C, Nacken W, Brinkmann V, Jungblut PR, Zychlinsky A (2009) Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathog 5(10):e1000639. https://doi.org/10.1371/journal.ppat.1000639 van der Sluis RM, Cham LB, Gris-Oliver A, Gammelgaard KR, Pedersen JG, Idorn M, Ahmadov U, Hernandez SS, Cémalovic E, Godsk SH, Thyrsted J, Gunst JD, Nielsen SD, Jørgensen JJ, Bjerg TW, Laustsen A, Reinert LS, Olagnier D, Bak RO, Kjolby M, Holm CK, Tolstrup M, Paludan SR, Kristensen LS, Søgaard OS, Jakobsen MR (2022) TLR2 and TLR7 mediate distinct immunopathological and antiviral plasmacytoid dendritic cell responses to SARS-CoV-2 infection. EMBO J 41(10):e109622. https://doi.org/10.15252/embj.2021109622 van der Vorst EPC, Mandl M, Müller M, Neideck C, Jansen Y, Hristov M, Gencer S, Peters LJF, Meiler S, Feld M, Geiselhöringer AL, de Jong RJ, Ohnmacht C, Noels H, Soehnlein O, Drechsler M, Weber C, Döring Y (2019) Hematopoietic ChemR23 (Chemerin Receptor 23) fuels atherosclerosis by sustaining an M1 macrophage-phenotype and guidance of plasmacytoid dendritic cells to murine lesions-brief report. Arterioscler Thromb Vasc Biol 39(4):685–693. https://doi.org/10.1161/ATVBAHA.119.312386 Veckman V, Julkunen I (2008) Streptococcus pyogenes activates human plasmacytoid and myeloid dendritic cells. J Leukoc Biol 83(2):296–304. https://doi.org/10.1189/jlb.0707457 Voisine C, Mastelic B, Sponaas AM, Langhorne J (2010) Classical CD11c+ dendritic cells, not plasmacytoid dendritic cells, induce T cell responses to Plasmodium chabaudi malaria. Int J Parasitol 40(6):711–719. https://doi.org/10.1016/j.ijpara.2009.11.005 Webster B, Assil S, Dreux M (2016) Cell-cell sensing of viral infection by plasmacytoid dendritic cells. J Virol 90(22):10050–10053. https://doi.org/10.1128/JVI.01692-16 Wieland SF, Takahashi K, Boyd B, Whitten-Bauer C, Ngo N, de la Torre JC, Chisari FV (2014) Human plasmacytoid dendritic cells sense lymphocytic choriomeningitis virus-infected cells in vitro. J Virol 88(1):752–757. https://doi.org/10.1128/JVI.01714-13 Williams NL, Morris JL, Rush CM, Ketheesan N (2015) Plasmacytoid dendritic cell bactericidal activity against Burkholderia pseudomallei. Microbes Infect 17(4):311–316. https://doi.org/10. 1016/j.micinf.2014.12.007 Woltman AM, Op den Brouw ML, Biesta PJ, Shi CC, Janssen HL (2011) Hepatitis B virus lacks immune activating capacity, but actively inhibits plasmacytoid dendritic cell function. PLoS One 6(1):e15324. https://doi.org/10.1371/journal.pone.0015324 Wu V, Smith AA, You H, Nguyen TA, Ferguson R, Taylor M, Park JE, Llontop P, Youngman KR, Abramson T (2016) Plasmacytoid dendritic cell-derived IFNα modulates Th17 differentiation during early Bordetella pertussis infection in mice. Mucosal Immunol 9(3):777–786. https://doi. org/10.1038/mi.2015.101 Xu Y, Hu Y, Shi B, Zhang X, Wang J, Zhang Z, Shen F, Zhang Q, Sun S, Yuan Z (2009) HBsAg inhibits TLR9-mediated activation and IFN-alpha production in plasmacytoid dendritic cells. Mol Immunol 46(13):2640–2646. https://doi.org/10.1016/j.molimm.2009.04.031 Yoshida M, Worlock KB, Huang N, RGH L, Butler CR, Kumasaka N, Dominguez Conde C, Mamanova L, Bolt L, Richardson L, Polanski K, Madissoon E, Barnes JL, Allen-Hyttinen J, Kilich E, Jones BC, de Wilton A, Wilbrey-Clark A, Sungnak W, Pett JP, Weller J, Prigmore E, Yung H, Mehta P, Saleh A, Saigal A, Chu V, Cohen JM, Cane C, Iordanidou A, Shibuya S, Reuschl AK, Herczeg IT, Argento AC, Wunderink RG, Smith SB, Poor TA, Gao CA, Dematte JE, NU SCRIPT Study Investigators, Reynolds G, Haniffa M, Bowyer GS, Coates M, Clatworthy MR, Calero-Nieto FJ, Göttgens B, O’Callaghan C, Sebire NJ, Jolly C, De Coppi P, Smith CM, Misharin AV, Janes SM, Teichmann SA, Nikolić MZ, Meyer KB (2022) Local and systemic responses to SARS-CoV-2 infection in children and adults. Nature 602(7896):321–327. https://doi.org/10.1038/s41586-021-04345-x

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Chapter 5

Plasmacytoid Dendritic Cells in Autoimmunity

The very ability of plasmacytoid dendritic cells (pDCs) to induce rapid and massive production of type I interferons (IFNs) as well as a number of proinflammatory cytokines in response to activation of the endosomal toll-like receptors (TLRs), TLR7 and TLR9, that recognize, respectively, DNA and RNA molecules of both pathogenic and host origin, makes these cells play often a key role in initiating autoreactive inflammation (Ganguly et al. 2013). Type I IFNs, as noted earlier too, are pleiotropic cytokines with diverse functions on different innate and adaptive immune cells, ranging from promoting conventional dendritic cell (cDC) activation, potentiating T cell clonal expansion, activating B cell class switching and antibody production, driving proinflammatory phenotypic switch in myeloid cells to endothelial cell activation, apart from its originally described function of driving antiviral gene transcription in the host cell types. Thus aberrant release of type I IFNs in large amounts in the tissue spaces poses a major threat of initiating an inflammatory cascade resulting in tissue damage (Reizis 2019; Ganguly 2018). Continual cellular turn-over in the body in different physio-pathological scenarios always makes the extracellular environment in tissue spaces replete with host-origin nucleic acids as the dying cells release their nuclear and mitochondrial contents to the exterior. There are myriad natural barriers to inadvertent activation of the nucleic acid-recognizing TLRs in pDCs and other PRRs by these self-origin ligands—from annexation of extracellularly released nucleic acids within membrane-bound collections in case of the physiological apoptotic cell death, abundance of extracellular nucleases that can digest the nucleic acids occurring outside the host cells, intracellular seclusion of the cognate receptors and the usual necessity of receptor maturation for ligand recognition. Despite such preventive contraptions it is now established that different pathologic contexts do allow such autoreactivity to happen, variably due to immunogenic cell deaths resulting in extracellular nucleic acid release, deficiency or dysfunction of the nucleases, availability of chaperone molecules (e.g., certain nucleic acid-binding proteins) or immune complexes containing nucleic acids that can access the intracellular compartments wherein the cognate receptors are expressed. In this chapter we will discuss such clinically relevant © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 D. Ganguly, Plasmacytoid Dendritic Cells, https://doi.org/10.1007/978-981-19-5595-2_5

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contexts and the diseases they are associated with, which will help us appreciate the immense role pDCs may play in the pathogenesis of such human diseases.

5.1

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a prototypical systemic autoimmune disease, affecting mostly females. The major pathologic characteristics of SLE are autoantibody response against nuclear antigens viz. double stranded DNA (dsDNA), RNA, RNA binding proteins. The resulting immune complexes get deposited in multiple organs as well as drive antibody-mediated cytotoxicity, interfering with tissue integrity and physiology leading to debilitating disease affecting skin, limb joints, vessels, central nervous system, and kidneys (Tsokos 2011). Classically SLE is described as a polygenic disease with genetic association with a complex array of gene families (Eyre et al. 2017). Monogenic afflictions reproducing the classical SLE disease are also reported, e.g. one affecting DNAse1L3, a DNAse specialized in digesting extracellular DNA (Al-Mayouf et al. 2011). Interestingly, DNAse1L3-targeting autoantibody response is also documented in non-monogenic SLE patients, pointing to the importance of this nuclease in mediating tolerance to self-DNA (Hartl et al. 2021). On the other hand, report of discordant monozygotic twins, with one sibling affected by SLE, also points to the important role epigenetic regulations may play in the pathogenesis (Javierre et al. 2010; Marion et al. 2021). Spontaneous lupus-like disease in mice, e.g. the NZBW-F1 strain (with several disease-associated loci in several chromosomes) and BXSB strain (with a duplication of a telomeric segment of the X chromosome onto the Y chromosome containing close to 19 genes including the gene for Tlr7), recapitulates the polygenic involvement in pathogenesis that can be transferred to wild type mice with transfer of the contigs mapped to be associated with the disease (Prud’homme et al. 1983; Morel et al. 1999). On the other hand, there are monogenic rodent models of lupus as well like the MRL/lpr mice (with mutation in the FAS receptor) and DNASE1L3 knockout mice (Pisetsky et al. 1980; Cohen and Eisenberg 1991; Sisirak et al. 2016). Autoreactive B cells driving an autoantibody response to predominantly nuclear antigens are long established pathogenetic keystones for SLE. Interestingly, a prominent role for type I IFNs has also been well established over last two decades or so. Of note, long before pDCs were identified to be the professional type I IFN producers, report of SLE patients with higher abundance of IFNs in circulation which correlated with their autoantibody response and disease activity was made way back in 1979 (Hooks et al. 1979). A renewed interest in the role of type I IFNs in SLE grew after demonstration of an enrichment of interferon signature gene (ISG) transcripts in the peripheral blood mononuclear cells from SLE patients (Bennett et al. 2003). The ISG enrichment was linked to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores in the patient. A more recent report also re-demonstrated that circulating IFN-α, present at attomolar concentrations, is

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Systemic Lupus Erythematosus

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significantly correlated with disease activity scores in SLE patients (Rodero et al. 2017). Genetic deficiency of type I IFN receptor (IFNAR1) has also been shown to protect against spontaneous lupus development in mice (Santiago-Raber et al. 2003). PDCs have been shown to be the key, if not the most important, source of type I IFNs in SLE (Motwani et al. 2021). In preclinical models of spontaneous lupus, either the polygenic model with large disease linked chromosomal regions or the mice with multiple copies of TLR7, lack of pDCs, either due to genetic deficiency of the transcription factors like IRF8 or E2-2, or on targeted depletion using the BDCADTR mice, has been shown to protect the animals from the disease (Baccala et al. 2013; Sisirak et al. 2014; Rowland et al. 2014). Immune complexes isolated from SLE patients contain self-origin DNA and RNA molecules and have been shown to activate TLR9 and TLR7, respectively (Barrat et al. 2005; Savarese et al. 2006). Corticosteroids are the key therapeutic agents for SLE patients and it has been demonstrated, both in vitro in human cells and in vivo with different mice models of lupus, that type I IFN induction in response to TLR7 or TLR9 activation in pDCs is resistant to corticosteroid activity (Guiducci et al. 2010). Dual antagonists of TLR9 and TLR7 have also been shown to ameliorate disease in a mouse model (Barrat et al. 2007). A role of steady-state tone of endocannabinoids in restricting TLR activation in pDCs has been demonstrated recently, which has also been shown to be disrupted in a subgroup SLE patients (Rahaman et al. 2019). While general assumption is an equally important role of TLR9 and TLR7 in pDC activation in the context of human SLE, experiments mice genetically deficient in these individual TLRs provided intriguingly distinctive data. In the MRL/lpr preclinical mouse model of lupus, as expected, genetic deficiency of TLR9 and TLR7 abrogated autoantibody response to dsDNA and RNA containing antigens, respectively (Christensen et al. 2005, 2006). More interestingly, TLR9 deficiency was shown to lead to a more aggressive disease activity, presumably due to overexpression of TLR7, while TLR7 deficiency largely ameliorated the disease in different preclinical models, perhaps pointing to a more critical role of TLR7 (Christensen et al. 2006; Santiago-Raber et al. 2010; Bossaller et al. 2016). Genetic deficiency of both TLR9 and TLR7 was able to ameliorate the disease development as expected. Clinically relevant corroboration of this data in humans is still awaited. But in this respect the species-specific differences in TLR9 and TLR7 expression and the role of TLR9 and TLR7 in directly activating B cells should also be kept into consideration, which may underlie these disparate effects of TLR9 and TLR7. Nevertheless, therapeutic targeting of endosomal TLRs in SLE, which are being explored as will be discussed in a later chapter, should logically consider targeting both the TLRs for clinical efficacy. The report on enrichment of ISG transcripts in the peripheral blood of SLE patients was also accompanied by data on enrichment of a number of signature transcripts of granulopoiesis (Bennett et al. 2003). This granulopoiesis signature was perhaps pointing to increased propensity of neutrophil death in SLE patients, which was also documented in other clinical studies as well (Midgley et al. 2009). At the same time a new type of cellular death mechanism was described in neutrophils in

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the context of bacterial infections, characterized by the release of cellular DNA as extracellular nets which could trap bacteria in tissue spaces (Brinkmann et al. 2004; Brinkmann and Zychlinsky 2021). This uniquely “functional” death in neutrophils has been named as NETosis. Interestingly, NETosis, has been directly observed in circulating neutrophils SLE patients (Lande et al. 2011; Garcia-Romo et al. 2011). DNA molecules released extracellularly in the NETosis process have been shown to activate TLR9 and induce type I IFN production in pDCs. This has been shown to be facilitated by association of the released DNA with endogenous carrier proteins, viz. the cathelicidin antimicrobial peptide LL37 and the DNA-binding protein high mobility group box 1 (HMGB1), as well as circulating anti-DNA autoantibodies (Lande et al. 2011; Ganguly et al. 2013). Later reports have implicated oxidized mitochondrial DNA for the TLR9 activation, which are present within the extracellular DNA traps released by the NETotic neutrophils (Caielli et al. 2016). Figure 5.1 shows the major innate and adaptive immunocellular events documented in the context of SLE. In the context of SLE, type I IFNs have been demonstrated to regulate multiple immune cells contributing to the systemic inflammation, viz. activation of inflammatory dendritic cells, T cells proliferation, activation and expansion of autoreactive B cells as well as inhibition and depletion of both regulatory T and B cells (Blanco et al. 2001; Braun et al. 2002; Golding et al. 2010; Kiefer et al. 2012; Menon et al. 2016; Wolf et al. 2019). PDCs and type I IFNs are thus established to be very important therapeutic targets in systemic lupus. Clinical trials with monoclonal antibodies that target either IFN-α (sifalimumab) or the type I IFN receptor (anifrolumab) have been undertaken in SLE, with anifrolumab showing very promising results in a phase 3 clinical trial (Khamashta et al. 2016; Morand et al. 2020). A humanized monoclonal antibody targeting the pDC molecule BDCA2 has also been developed and in a randomized phase 1 trial in a small cohort of patients this antibody has been shown to be considerably safe and was efficacious in terms of reducing ISG expression in the peripheral blood cells, inflammation in the skin lesions as well as reducing the clinical score of the disease (Furie et al. 2019). The JAK inhibitor tofacitinib has been shown to inhibit type I IFN induction by pDCs and is also being tested in clinical trials in SLE patients (Boor et al. 2017; Hasni et al. 2021). Finally, drugs targeting specific endosomal TLRs in pDCs are also being actively pursued worldwide (Talukdar et al. 2021).

5.2

Psoriasis

Psoriasis is a chronic cutaneous inflammatory disease, with limb joint inflammation and tissue damage in severely affected patients. Plaque psoriasis, the most common form, leads to raised, red lesions with silvery white scales (due to accumulation of dead keratinocytes) and is histologically characterized by hyper-proliferating keratinocytes leading to epidermal thickening and elongation of dermal papillae (acanthosis), neoangiogenesis and conspicuous inflammatory infiltrate (Nestle et al.

Psoriasis

Fig. 5.1 Role of plasmacytoid dendritic cells in innate initiation of pathogenesis in systemic lupus erythematosus. The NETotic cell death of neutrophils or extracellular nucleic acids bound to antimicrobial peptides from other sources provides with the nucleic acid ligands for endosomal toll-like receptors in plasmacytoid dendritic cells, leading to induction of type I interferons. Type I interferons in turn promote T cell priming and autoreactive B cell expansion. Autoantibodies bound to nuclear antigens in immune complexes further enhance toll-like receptor activation in plasmacytoid dendritic cells. Autoantibodies also promote NETosis in neutrophils. (Reproduced with permission from Ganguly D et al., 2013)

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2009; Lowes et al. 2007). The disease course is known to be localized predominantly to friction points on the skin or skin folds and influenced by environmental factors (viz. seasonal changes) and occurrence of physical trauma. Local injuries are reported to trigger exacerbations of the lesions, called Koebner’s phenomenon (Eyre and Krueger 1982). Infection of the involved skin in psoriasis is rare, at times explained by an unusually high expression of different antimicrobial peptides in the psoriatic epidermis (Schittek et al. 2008). Genetic predisposition to psoriasis in family studies is documented though the inheritance patterns are unclear (Henseler and Christophers 1985). Concordance among monozygotic twins is reported to be around 70%, the same among dizygotic twins being 20%, supporting genetic associations (Farber et al. 1974). First-degree and second-degree relatives of patients are known to be have predispositions to the disease too (Farber et al. 1974; Morris et al. 2001). In the pathogenesis of psoriasis, a crucial role of T cells (both CD4+ and CD8+ effector T cells and γδ T cells) that produce IL-17 and IL-22 and recruitment and activation of cDCs driving the autoreactive proinflammatory T cells in situ are well established (Lowes et al. 2007; Cai et al. 2011; Ganguly et al. 2013). The autoimmune character of psoriasis has been debatable until very recently (Nestle et al. 2009; Lande et al. 2014). The innate initiation of inflammation was reported to involve skin recruitment and in situ activation of pDCs leading to induction of type I IFNs (Nestle et al. 2005). Chemerin, a pDC-specific chemokine, has been shown to be highly expressed psoriatic lesions leading to recruitment of pDCs to skin through its chemokine like receptor 1 (CMKLR1), the cognate receptor for chemerin (Albanesi et al. 2009). Psoriatic skin was demonstrated to have a very high expression of the human cathelicidin LL37 as well as other antimicrobial peptides (Lande et al. 2007, 2015). Extracellular nucleic acids, both DNA and RNA, are abundant in psoriatic skin due to characteristically prolific turn-over of keratinocytes (Ganguly et al. 2009). Interestingly, it was demonstrated that cationic antimicrobial peptides can bind and transport these endogenous nucleic acid molecules, both DNA and RNA, into the pDC endosomes and trigger activation of TLR9 and TLR7 as well as induction of type I IFNs (Lande et al. 2007, 2015; Gilliet and Lande 2008; Ganguly et al. 2009; Antal et al. 2022). Subsequently, LL37 was also shown to get targeted as an autoantigen in psoriasis by antigen-specific effector T cells (Lande et al. 2014). Role of complement pathway constituents in autoimmune diseases is a growing field of interest, mostly due to expected involvement of this pathway in autoantibody-induced end organ damage (Chen et al. 2010; Ballanti et al. 2013). Circulating mannose binding lectin (MBL) levels have been reported to be associated with psoriasis in the preclinical model of imiquimod-induced disease (Zeng et al. 2019). But if such complement components can directly affect earlier pathogenetic events involving regulation of pDC abundance and function is not much explored. Attachment of MBL on the cell surface of invading microorganisms leading to activation of complement cascade is one of the three pathways of complement system in our body. A recent study reported a rather interesting direct effect of MBL on pDCs (Zeng et al. 2022). Circulating MBL level was found to be correlated with severity of psoriatic disease, circulating inflammatory cytokines as

5.2

Psoriasis

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Fig. 5.2 Role of plasmacytoid dendritic cells in innate initiation of pathogenesis in psoriasis. Expression of antimicrobial peptides, viz. LL37, in skin that bind extracellular nucleic acids and get access to the endosomal toll-like receptors (TLR7 and TLR9) in plasmacytoid dendritic cells drive a local type I interferon response which in turn activate conventional dendritic cells and potentiate T cell priming. Similarly, RNA molecules bound to LL37 have been shown to activate endosomal toll-like receptor TLR8 in conventional dendritic cells driving activation. These culminates in a prominent T cell mediated autoimmunity characterized by local production of IL-17 and IL-22 from T cells. (Reproduced with permission from Antal D et al., 2022)

well as pDC frequency in patients. Ex vivo generation of pDCs from bone marrow cells in response to FLT3L was deficient in mice genetically deficient in MBL. Moreover, MBL-KO mice genetically deficient in MBL had lower abundance of pDCs in skin lesions as well as secondary lymphoid organs in the initial stages of imiquimod-induced psoriasis. Effect on STAT3 and IRF8 signaling axis was found to be responsible for these effects of MBL. Figure 5.2 displays the architecture of the cutaneous inflammation in psoriasis. In conclusion, the endosomal TLRs in pDCs and the type I IFN pathway can also be potentially targeted for therapy in psoriasis, apart from the IL-17 pathway which is the major target of anti-psoriatic biologic therapies.

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Systemic Sclerosis

Systemic sclerosis (SSc) is an autoimmune systemic disease which mostly affects the connective tissues in skin and subcutaneous tissues, blood vessels, muscles as well as organs like lungs, heart, kidney. Central nervous system and gut is also affected in subgroups of patients. The major pathologic feature is widespread fibrosis associated with chronic inflammation, which leads to tissue specific clinical outcomes. The interest on role of pDCs and type I IFNs in SSc was triggered again by the documentation of prominent interferon signature gene (ISG) expression in peripheral blood cells as well as affected tissues in patients (York et al. 2007; Assassi et al. 2010; York 2011; Higgs et al. 2011; Christmann et al. 2014). ISG enrichment, in both blood cells and affected tissues (e.g., lungs), seems to precede the fibrotic disease (Brkic et al. 2016). Genetic association studies in this disease, which is again documented to be a complex genetic disorder, also reveal genes involved in type I IFN induction and functions to be associated with the disease (Gorlova et al. 2011; Sharif et al. 2012; Mayes et al. 2014; Mahoney et al. 2015). PDCs as the major producers of type I IFNs is also appreciated in SSc. In a subgroup of patients who present with skin-restricted fibrotic response also known as scleroderma, pDCs infiltration in the lesions and in situ induction of type I IFNs are documented (Ghoreishi et al. 2012; Ah Kioon et al. 2018). A few studies suggested role of specific micro-RNAs (viz. miRNA-618; miRNA-126, miRNA-1395p) in regulating pDC activation in SSc, IRF8 being identified as one of the relevant targets and an increase in type I IFN induction being the most relevant outcome (Rossato et al. 2017; Chouri et al. 2021). Another study has implicated reduced expression of the transcription factor RUNX3 in pDC dysregulation in a preclinical model of SSC (Affandi et al. 2019). Specific dysregulations of such molecular regulators in pDCs in the context of SSC is far from fully understood and is an active area of research. Interestingly, apart from the type I IFNs, pDCs infiltrating sclerotic lesions have also been found to produce the chemokine CXC-chemokine ligand 4 or CXCL4 (van Bon et al. 2014; Ah Kioon et al. 2018). Proteomics analyses showed CXCL4 to be a predominant protein as part of the pDC secretome in large cohorts of SSc patients and production of CXCL4 by pDCs has been shown to be directly linked to disease activity and contributing to the fibrogenic response (van Bon et al. 2014). Mechanistically, pDCs in SSc express TLR8, unlike healthy pDCs or even pDCs from SLE patients, and TLR8 activation play a major role in CXCL4 expression by pDCs. CXCL4 in turn was shown to potentiate IFN-α production in response to both TLR9 and TLR8 activation (Ah Kioon et al. 2018). Interestingly, CXCL4 has also found to bind self-DNA molecules and activate TLR9 in human pDCs, thus driving a type I IFN response (Lande et al. 2019). Such CXCL4-DNA complexes were also demonstrated in vivo in patients. In addition, an autoantibody response against CXCL4 has also been reported in SSc patients, which correlated with systemic type I IFN response as well as fibrotic pathology in two cohorts (Lande et al. 2020). It has also been reported that SSc patients with autoantibodies to certain antigens, viz. SSB/Ro, U1 RNP, topoisomerase, more often have prominent systemic type I IFN response

5.3

Systemic Sclerosis

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Fig. 5.3 Immunocellular crosstalks in the pathogenesis of systemic sclerosis. Autoantibodies produced by autoreactive B cells help nuclear antigens to get access to the endosomal toll-like receptors in plasmacytoid dendritic cells inducing a local type I interferon response and CXCL4 production. This in turn accentuates priming of T cells and proinflammatory cytokine production by conventional dendritic cells, autoreactive B cell expansion, and fibroblast activation driving tissue inflammation and fibrosis. (Reproduced with permission from Affandi AJ et al., 2018)

than patients without these antibodies (Assassi et al. 2010; Wuttge et al. 2013). This plausibly indicates immune complex driven pDC activation, which is also encountered in other autoimmune diseases (Affandi et al. 2018). Altogether, pDCs are identified to be a key immune cell in the crossroads of interactions between the innate immune cells, adaptive immune response as well as the tissue response (Fig. 5.3). Thus, pDCs and pDC-derived type I IFNs as well as CXCL4 are being explored as potential therapeutic targets in SSc. The monoclonal antibody against type I IFN receptor anifrolumab has been tried in a phase 1 clinical trial in SSc patients, showing reduced T cell activation and collagen deposition (Guo et al. 2015). Further clinical trials in this domain are still awaited.

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Sjogren’s Syndrome

A role of pDCs and pDC-derived type I IFNs has also been documented in the context of Sjogren’s syndrome (SS), an autoimmune disease with characteristic humoral autoreactivity and circulating autoantibodies, that primarily affects exocrine glands in the body, e.g. salivary glands and lacrimal glands (Mariette and Criswell 2018; Verstappen et al. 2021; Yao et al. 2013). In situ inflammation and dysfunction lead to varied clinical presentations depending on the dominant tissue involvement, with patients variably presenting with dryness of mouth (decreased salivation), dry eye (deficient lacrimation), fatigue, and body ache (Pontarini et al. 2021; Mariette and Criswell 2018). Patients with SS have also been shown to have an increased risk of developing B cell lymphomas (Verstappen et al. 2021; Kapsogeorgou et al. 2019). A focus on involvement of pDCs and type I IFNs in SS pathogenesis resulted from data on induction of type I IFNs from human pDCs in response to sera from SS patients, detection of IFN-α and ISG gene transcripts in the affected tissues (Båve et al. 2005; Hjelmervik et al. 2005) and pDC recruitment in the affected tissues (Gottenberg et al. 2006). Circulating abundance of activated CD40-expressing pDCs was found to be strongly correlated with ISG expression in circulating monocytes in SS patients (Wildenberg et al. 2008). On the other hand a reduction in circulating pDCs is also noted in SS patients, presumably due to recruitment in target organs (Vogelsang et al. 2010). A recent study in a preclinical SS model, using female non-obese diabetic (NOD) mice, provided the in vivo loss-of-function evidence for critical involvement of pDC-derived type I IFNs in SS (Zhou et al. 2022). Apart from documentation of type I IFN induction in the salivary glands in this preclinical SS model, on administration of a pDC-depleting monoclonal antibody there was marked abrogation of inflammation and secretory dysfunction of the salivary glands, reduction in type I IFN and ISG transcript expression as well as reduced recruitment of T and B cells. Figure 5.4 describes the central role of pDCs in driving autoreactive inflammation in SS based on available data (Kroese and Bootsma 2013). Animal models with genetic deficiency pDCs and type I IFN signaling, like the ones used in case of lupus, along with longer term preclinical models of SS that more closely mimics human SS, will be useful in establishing this innate pathogenetic event in SS and identifying novel therapeutic targets.

5.5

Role of pDCs in Other Major Rheumatological Disorders

A number of other rheumatological disorders have also been shown to involve a major pathogenetic component involving pDC activation and systemic as well as local type I IFN response (Muskardin and Niewold 2018). Among them we discuss a

5.5

Role of pDCs in Other Major Rheumatological Disorders

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Fig. 5.4 Role of plasmacytoid dendritic cells in the pathogenesis of Sjogren syndrome. Nucleic acid ligands of host or pathogenic origins activate endosomal toll-like receptors in plasmacytoid dendritic cells driving type I interferon response, which in turn accentuate T cell priming as well as expansion and maintenance of autoreactive B cells. (Reproduced with permission from Kroese FG and Bootsma H, 2013)

few, viz. myositis, autoimmune pancreatitis, and rheumatoid arthritis, as data in these contexts are more abundant than others. Myositis, as the name suggests, refers to the chronic inflammation in the muscle tissue and a major subset of such occurrences have autoimmune inflictions. Both polymyositis (chronic inflammation affecting multiple muscles in the body) and dermatomyositis (a condition with involvement of both skin and multiple muscles) have been reported to be associated with a systemic type I IFN response, with the magnitude of type I IFN response shown to be correlated with disease activity in multiple studies (O’Connor et al. 2006; Niewold et al. 2009; Reed et al. 2012; Greenberg et al. 2012). Muscle biopsies or skin also show infiltration of pDCs in patients with dermatomyositis (McNiff and Kaplan 2008; Shrestha et al. 2010). Accordingly, TLR9 and TLR7 activation has been also linked to type I IFN response in myositis (Kim et al. 2010; Cappelletti et al. 2011). Of note, a recent phase 2 clinical trial on using a TLR7 and TLR9 dual antagonist IMO-8400 failed to show any clinical benefit in dermatomyositis (Kim et al. 2021). Thus further studies are warranted to decipher the role of pDC activation and type I IFN induction in pathogenesis and therapeutic targeting of this pathway in myositis. Rheumatoid arthritis (RA) is the most common autoimmune disease affecting the joints causing chronic inflammation (or arthritis). RA mostly affects small joints in hand and feet in the early stages, but more severe disease also involves bigger joints like knee and shoulder. Unabated chronic inflammation in the joints in some patients leads to deformities and considerable interference with daily life. Autoreactive B

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cells have been the keystone of RA pathogenesis with autoantibodies against synovial antigens, leading to joint inflammation (Lübbers et al. 2015; Scherer et al. 2022). Nevertheless, systemic type I IFN induction is also documented to be associated with disease activity in RA and is assumed to be an initial event in pathogenesis as subclinical disease is often associated with such IFN responses (Higgs et al. 2011; Lübbers et al. 2013). Genetic association studies also reveal association of genes involved in IFN response, often shared with other major autoimmune diseases (Dieguez-Gonzalez et al. 2008; Remmers et al. 2007). Local recruitment of pDCs and type I IFN induction in situ are also reported by several early studies (Lande et al. 2004; Cavanagh et al. 2005). Interestingly, another set of evidence suggest an increase in pDC generation from bone marrow and proliferation of peripheral pDCs in patients with RA (Hirohata et al. 2014; Cooles et al. 2018). Circulating pDCs in RA were found to be in a more unactivated state, raising questions whether they are involved in the inflammation (Cooles et al. 2018). Whether pDCs do play a critical pathogenetic role in RA by means of type I IFN induction as a major cellular source of these cytokines, or by exerting a rather anti-inflammatory effect thus remains to be established. Indeed, in preclinical models of RA pDC depletion was found to exacerbate disease and TLR7-agonist treatment leading to local induction of type I IFNs was found to be beneficial (Nehmar et al. 2017). Immunoglobulin G4-related disease (IgG4-RD) is a rather newly described family of chronic inflammatory disease sharing the common pathognomonic feature of elevated serum IgG4 concentration (Stone et al. 2012). The inflammation, characterized by infiltration of IgG4+ plasma cells, ensues in different organs, viz. pancreas, salivary glands, bile ducts, thyroid glands or brain meninges, followed often by a fibrotic response (Deshpande et al. 2012; Shapiro et al. 2012; Stone et al. 2012; Ohara et al. 2013; Kamisawa et al. 2013). Thus the patients variably present with pancreatitis, sialadenitis, cholangitis, thyroiditis, or meningitis based on the particular organ involved. In a preclinical model of autoimmune pancreatitis in MRL/lpr mice injected intraperitoneally with TLR3 agonist, a prominent infiltration of pDCs and in situ induction of type I IFNs were linked to pancreatitis. A role of NETosis was also revealed which provided pDCs with TLR9 ligands (Arai et al. 2015). PDC depletion could ameliorate the pancreatic inflammation in this model. Patients with IgG4-related autoimmune pancreatitis also showed NETosis, pDC infiltration, and type I IFN induction in pancreas (Arai et al. 2015). In this preclinical model the fibrotic response was also ameliorated by pDC depletion. Interestingly, pDCs infiltrating the pancreas were found to express IL-33 in response to TLR9 activation, in addition to type I IFNs, in an IFNAR dependent manner (Watanabe et al. 2017). In patients with IgG4-related pancreatitis circulating type I IFNs and IL-33 have been found to be increased and correlated with IgG4 levels (Minaga et al. 2020). Thus pDCs and type I IFNs plausibly play a critical role in IgG4-related diseases and will be interesting to explore in different clinical contexts of this disease.

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Apart from the originally appreciated critical role of pDCs and pDC-derived type I IFNs in infectious contexts, especially in the context of viral infections, over last two decades or so a very crucial role of pDC activation as an important innate initiation event in chronic inflammation encountered in different autoimmune diseases has been realized. Insights gathered on the role of pDCs in different autoimmune contexts have also led to the identification of novel therapeutic targets, some of which already have shown potential clinical benefits.

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Kroese FG, Bootsma H (2013) Biomarkers: new biomarker for Sjögren’s syndrome—time to treat patients. Nat Rev Rheumatol 9(10):570–572. https://doi.org/10.1038/nrrheum.2013.143 Lande R, Giacomini E, Serafini B, Rosicarelli B, Sebastiani GD, Minisola G, Tarantino U, Riccieri V, Valesini G, Coccia EM (2004) Characterization and recruitment of plasmacytoid dendritic cells in synovial fluid and tissue of patients with chronic inflammatory arthritis. J Immunol 173(4):2815–2824. https://doi.org/10.4049/jimmunol.173.4.2815 Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang YH, Homey B, Cao W, Wang YH, Su B, Nestle FO, Zal T, Mellman I, Schröder JM, Liu YJ, Gilliet M (2007) Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449(7162):564–569. https:// doi.org/10.1038/nature06116 Lande R, Ganguly D, Facchinetti V, Frasca L, Conrad C, Gregorio J, Meller S, Chamilos G, Sebasigari R, Riccieri V, Bassett R, Amuro H, Fukuhara S, Ito T, Liu YJ, Gilliet M (2011) Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci Transl Med 3(73):73ra19. https://doi.org/10.1126/ scitranslmed.3001180 Lande R, Botti E, Jandus C, Dojcinovic D, Fanelli G, Conrad C, Chamilos G, Feldmeyer L, Marinari B, Chon S, Vence L, Riccieri V, Guillaume P, Navarini AA, Romero P, Costanzo A, Piccolella E, Gilliet M, Frasca L (2014) The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis. Nat Commun 5:5621. https://doi.org/10.1038/ncomms6621 Lande R, Chamilos G, Ganguly D, Demaria O, Frasca L, Durr S, Conrad C, Schröder J, Gilliet M (2015) Cationic antimicrobial peptides in psoriatic skin cooperate to break innate tolerance to self-DNA. Eur J Immunol 45(1):203–213. https://doi.org/10.1002/eji.201344277 Lande R, Lee EY, Palazzo R, Marinari B, Pietraforte I, Santos GS, Mattenberger Y, Spadaro F, Stefanantoni K, Iannace N, Dufour AM, Falchi M, Bianco M, Botti E, Bianchi L, Alvarez M, Riccieri V, Truchetet ME, Wong GCL, Chizzolini C, Frasca L (2019) CXCL4 assembles DNA into liquid crystalline complexes to amplify TLR9-mediated interferon-α production in systemic sclerosis. Nat Commun 10(1):1731. https://doi.org/10.1038/s41467-019-09683-z Lande R, Mennella A, Palazzo R, Pietraforte I, Stefanantoni K, Iannace N, Butera A, Boirivant M, Pica R, Conrad C, Chizzolini C, Riccieri V, Frasca L (2020) Anti-CXCL4 antibody reactivity is present in systemic sclerosis (SSc) and correlates with the SSc Type I interferon signature. Int J Mol Sci 21(14):5102. https://doi.org/10.3390/ijms21145102 Lowes MA, Bowcock AM, Krueger JG (2007) Pathogenesis and therapy of psoriasis. Nature 445(7130):866–873. https://doi.org/10.1038/nature05663 Lübbers J, Brink M, van de Stadt LA, Vosslamber S, Wesseling JG, van Schaardenburg D, Rantapää-Dahlqvist S, Verweij CL (2013) The type I IFN signature as a biomarker of preclinical rheumatoid arthritis. Ann Rheum Dis 72(5):776–780. https://doi.org/10.1136/annrheumdis2012-202753 Lübbers J, Vosslamber S, van de Stadt LA, van Beers-Tas M, Wesseling JG, von Blomberg BM, Witte BI, Bontkes HJ, van Schaardenburg D, Verweij CL (2015) B cell signature contributes to the prediction of RA development in patients with arthralgia. Ann Rheum Dis 74(9):1786–1788. https://doi.org/10.1136/annrheumdis-2015-207324 Mahoney JM, Taroni J, Martyanov V, Wood TA, Greene CS, Pioli PA, Hinchcliff ME, Whitfield ML (2015) Systems level analysis of systemic sclerosis shows a network of immune and profibrotic pathways connected with genetic polymorphisms. PLoS Comput Biol 11(1): e1004005. https://doi.org/10.1371/journal.pcbi.1004005 Mariette X, Criswell LA (2018) Primary Sjögren’s syndrome. N Engl J Med 378(10):931–939. https://doi.org/10.1056/NEJMcp1702514 Marion MC, Ramos PS, Bachali P, Labonte AC, Zimmerman KD, Ainsworth HC, Heuer SE, Robl RD, Catalina MD, Kelly JA, Howard TD, Lipsky PE, Grammer AC, Langefeld CD (2021) Nucleic acid-sensing and interferon-inducible pathways show differential methylation in MZ twins discordant for lupus and overexpression in independent lupus samples: implications for pathogenic mechanism and drug targeting. Genes (Basel) 12(12):1898. https://doi.org/10.3390/ genes12121898

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Chapter 6

Plasmacytoid Dendritic Cells and Metabolic Disorders

A major metabolic disorder with autoimmune infliction is type 1 diabetes mellitus, affecting the young and leading to insulin-dependent diabetes. On the other hand, metabolic disorders as well as obesity have become a major disease burden all over the world and altogether are projected to involve more than two billion people worldwide. The three most important contexts of a metabolic syndrome are systemic insulin resistance usually in presence but also in absence of obesity, different grades of chronic liver disease (mostly featuring fatty degeneration and chronic inflammation) and cardiovascular diseases notably including atherosclerosis and hypertension. These complex set of disorders are combined within the syndromic description as these are clinically presented in isolation as well as, quite often in combinations. It is well-known that insulin-dependent diabetes is a result of autoreactive inflammation in the pancreas leading to islet destruction. Over the past two decades or so a major area of research in the domain of metabolic syndrome has also been the role of chronic low grade inflammation in the metabolic tissues, viz. visceral adipose tissue, liver, as well as in the blood vessels, which critically contribute to the metabolic derangements encountered. However, the classical description of autoimmunity, with identified autoantigens, does not fit into the pathogenesis. Nevertheless, studies have shown that different immune cells infiltrate the metabolic tissues and drive induction of proinflammatory cytokines in situ in metabolic disorders. In the steady state too the metabolic tissues have immune cells, but with functional inclinations that prevent inflammation. In this chapter we will revisit the nature of role pDCs play in autoimmune diabetes as well as in the low grade but long-standing inflammatory going-ons in different metabolic tissues in different clinical contexts of metabolic syndrome (also referred to as metaflammation) and gather insight on how plasmacytoid dendritic cells (pDCs) and type I interferons (IFNs) released by them play a role in orchestrating metaflammation.

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 D. Ganguly, Plasmacytoid Dendritic Cells, https://doi.org/10.1007/978-981-19-5595-2_6

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Type 1 Diabetes Mellitus

The autoimmune disease affecting the β cells in the pancreatic islets, wherein inflammatory damage to the islets lead to deficiency in insulin production and diabetes mellitus (type 1 diabetes mellitus or T1DM), has also been shown to involve in situ pDC activation which play a major role in the initiation of inflammation. The islet damage in T1DM is established to be driven by autoreactive effector T cells and the disease does have documented genetic predispositions (Concannon et al. 2009). Major evidences for a role for type I IFNs in T1DM pathogenesis came from studies that documented expression of IFN-α in pancreatic islets in patients (Huang et al. 1995). Similar expression of type I IFNs in the inflamed pancreas was also documented in the preclinical models of the disease in mice (Huang et al. 1994; Li et al. 2008). This in situ induction of IFN-α has been proposed to be the innate initiation event in T1DM, as systemic blockade of IFNAR1 using a monoclonal antibody in the non-obese diabetic mice (NOD mice, the preclinical spontaneous model of T1DM) delayed the onset and reduced incidence of T1DM (Li et al. 2008). In a study on T1DM patients, it was reported that pDC frequency in circulating blood increases close to disease onset and pDCs were found to be able to capture islet autoantigenic immune complexes and prime autoantigen-specific CD4 T cells (Allen et al. 2009). In the preclinical model of the disease in NOD mice pDCs have been shown to infiltrate the islets. In NOD mice autoreactive B cells produce antiDNA autoantibodies that have been shown to induce NETosis in neutrophils also recruited to the islets. Extracellular DNA released in the NETosis process in turn activate TLR9 in pDCs and drive type I IFN production, as shown in SLE as well (Diana et al. 2013; Creusot 2013). This sequence of events was demonstrated to be crucial for generation of diabetogenic autoreactive T cells and islet destruction (Fig. 6.1). In fact, pDCs seem to be more efficient, as compared to cDCs, in presenting islet β cell antigens to T cells and thus driving diabetogenic autoreactive T cell response (Allen et al. 2009). Interestingly, antibody-mediated depletion of HMGB1 was found in another study to reduce T1DM pathogenesis in preclinical model, pointing to potential role of HMGB1 as a danger signal, plausibly acting through acting as carrier for extracellular nucleic acid ligands (Han et al. 2008). Whether pDCs and type I IFNs can be explored as therapeutic targets in T1DM remains to be further elucidated (Ganguly 2018).

6.2

Obesity and Type 2 Diabetes

Interest in adipose tissue inflammation in obese individuals grew after it was found that visceral adipose tissues (VAT) are infiltrated by macrophages with an inflammatory (M1 type) functional phenotype (Weisberg et al. 2003). In addition, it was found that in lean individuals VAT is infiltrated by immune cells with antiinflammatory functions, most importantly the regulatory T cells (Tregs), which are

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Obesity and Type 2 Diabetes

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Fig. 6.1 Plasmacytoid dendritic cells as an immunocellular player in islet inflammation in type 1 diabetes. Initiation of pancreatic pathology involves release of self-origin DNA and beta cell antigens from the beta cells as well as local NETotic cell death of neutrophils. The nucleic acid ligands thus released activate endosomal toll-like receptors in plasmacytoid dendritic cells driving type I interferon induction. Type I interferons in turn promote activation of macrophages and conventional dendritic cells in situ as well as T cell and B cell autoreactivity against beta cells. (Reproduced with permission from Creusot RJ, 2013)

strikingly depleted with hyperadiposity in obese individuals (Feuerer et al. 2009). Evidence from both preclinical models and human patients made these two findings the keystone of cellular architecture of metaflammation in obesity (Gregor and Hotamisligil 2011). Recruitment of pDCs in the visceral adipose tissue in obesity has been documented by several studies (Stefanovic-Racic et al. 2012; Bertola et al. 2012; Ghosh et al. 2016; Li et al. 2021). Interestingly, in a study on human VAT it was found that there is a prominent interferon signature gene expression in obese individuals and this played a critical role in proinflammatory switching of VAT-recruited macrophages (Ghosh et al. 2016). As a source of the type I IFNs in VAT pDCs were implicated, which are recruited to VAT in response to the chemokine chemerin, expressed by adipose tissue in obesity. In situ activation of the VAT-recruited pDCs was shown to be due to TLR9 activation in response to HMGB1-bound self-DNA molecules that are abundant in obese VAT extracellularly plausibly due to high cell turn-over (Ghosh et al. 2016; Nishimoto et al. 2016). Interestingly, mice deficient in RAGE, the receptor for HMGB1 are reported to be protected from high fat diet (HFD)-induced obesity and insulin resistance (Tian et al. 2007; Song et al. 2014). Another study confirmed the critical role of pDC-derived type I IFNs in the same HFD-induced preclinical obesity model that genetic deficiency of E2-2 leading to absence of pDCs as well as genetic deficiency of type I IFN receptor leading to

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Fig. 6.2 Role of plasmacytoid dendritic cells in adipose tissue inflammation in obesity. Plasmacytoid dendritic cells are recruited to obese visceral adipose tissue in response to chemerin released by adipocytes. Release of self-nucleic acids in the visceral adipose tissue in obesity get access to the endosomal toll-like receptors in plasmacytoid dendritic cells on being bound by proteins like HMGB1 and utilizing receptors like RAGE. In situ activation of plasmacytoid dendritic cells lead to type I interferon production which in turn drive proinflammatory polarization of the adipose recruited macrophages and inhibit adipose-resident T regulatory cells, thus promoting an inflammatory milieu in the visceral adipose tissue. (Image by Dipyaman Ganguly, 2022)

systemic absence of type I IFN signaling also protect mice from obesity and insulin resistance development (Hannibal et al. 2017). Genetic deficiency of the endosomal TLRs also have been shown to protect mice from HFD-induced obesity and insulin resistance (Revelo et al. 2016). In preclinical model a role of VAT-recruited pDCs in depleting Tregs through type I IFN signaling has also been reported recently to contribute to this pathogenetic role in obesity-associated insulin resistance (Li et al. 2021). Another recent study documented increased abundance and migratory speed of pDCs in obese VAT by intravital microscopy, which was found to be dependent upon P-selectins, as well as L- and E-selectins in response to HFD, engaging α4β1 and α4β7 integrins (Stutte et al. 2022). Thus a crucial role of pDCs in initiating and driving adipose tissue inflammation in obesity by affecting the other two cellular participants, viz. macrophages and Tregs, is apparent from several studies now (Fig. 6.2). Whether they can be targeted with therapeutic intention in insulin resistance associated with obesity remains to be explored in clinical studies.

6.3

6.3

Cardiovascular Components of Metabolic Syndrome

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Cardiovascular Components of Metabolic Syndrome

The major components in the cardiovascular dimension of metabolic syndrome are atherosclerosis, led from vessel wall inflammation eventually leading to narrowing of arteries due to lipid-laden plaques on the walls. The plaques may in turn lead to severe narrowing of vascular lumen causing circulatory compromise, may incite localized blood coagulation thus complicating the physical barrier to blood flow or may even lead to plaque rupture releasing circulating plaque fragments or microthrombi posing danger of microvascular blockade. Atherosclerosis is initiated by endothelial inflammation with upregulation of adhesion molecules that recruits immune cells to the endothelium (Geovanini and Libby 2018). Cholesterol deposition at the endothelium and their uptake by macrophages, forming of the so-called foam cells, play the pivotal role in atherosclerotic plaques (Galkina and Ley 2009). This also polarizes macrophages to a proinflammatory phenotype at the vascular intima, and type I IFNs have been implicated in both the recruitment and proinflammatory polarization of macrophages in the vessel wall (Niessner et al. 2007; Goossens et al. 2010; Moore et al. 2013). Macrophage-specific genetic deficiency of the type I IFN receptor has been shown to protect mice from development of atherosclerosis in a preclinical model, thereby implicating a role of type I IFNs possibly in the proinflammatory polarization of the recruited macrophages (Goossens et al. 2010). The endothelial dysfunction in terms of failure to prevent local thrombogenesis and inflammatory cell recruitment as well as the functional phenotype of macrophages, uptaking low density cholesterols (LDL) to form foam cells, may also be promoted by local type I IFN induction, thus contributing to the initiation of pathogenesis (Du et al. 2019). Single cell transcriptome analyses sequencing studies done on plaquerecruited macrophages reveal a prominent ISG expression profile that is linked to more severe pathology (Lin et al. 2019). PDCs have also been shown to get recruited to the plaques in patients with atherosclerosis in their carotid arteries and produce type I IFNs in situ (Niessner et al. 2006, 2007). Moreover, in patients with atherosclerosis of their coronary arteries there is a prominent reduction in the frequency of circulating pDCs which is associated with higher risk of clinical complications (Van Brussel et al. 2011; Van Vré et al. 2011). In the preclinical model of atherosclerosis in mice with apolipoprotein E genetic deficiency also pDC recruitment into the atherosclerotic plaque was documented and monoclonal antibody-mediated depletion of pDCs was shown to ameliorate the pathology (Döring et al. 2012; Macritchie et al. 2012). A more stringent model, using genetic deficiency of E2-2 for making mice deficient in pDCs, also confirmed this critical pathogenetic role of pDCs (Sage et al. 2014). It was also found that in situ activation of pDCs happen via recognition of self-DNA, released by NETotic death of neutrophils and bound to antimicrobial peptide LL-37, and antigen presentation to CD4+ T cells by pDCs through MHC class II was involved in the pathogenetic role of pDCs in this preclinical model (Döring et al. 2012; Sage et al. 2014; Zhang et al. 2015). In patients with atherosclerosis there is an abundance

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of circulating LL37-DNA complexes in circulation (Zhang et al. 2015). It has also been shown that there is anti-double stranded DNA autoantibody response in atherosclerosis (Döring et al. 2012). Thus a crucial role of pDC-derived type I IFNs is established as a plausible innate immune initiation event in atherosclerotic disease.

6.4

Fatty Liver Disease and Hepatic Metaflammation

Non-alcoholic fatty liver disease or NAFLD is another major component of metabolic syndrome, the major pathology being abnormal fatty depositions in the liver, followed by chronic hepatic inflammation and metabolic derangements, which eventually may lead cirrhosis of liver. Thus fatty depositions (known as hepatic steatosis) developing into frank hepatic inflammation (the so-called non-alcoholic steatohepatitis or NASH) and this in turn leading to hepatic cirrhosis constitute the pathologic spectrum. There is evidence of hepatic infiltration of proinflammatory immune cells as well as activation of liver resident myeloid cells (viz. Kupffer cells), culminating in the chronic inflammatory state in the hepatic microenvironment (Barreby et al. 2022). A role of endosomal TLR activation is established in preclinical models of NASH. Mice deficient in TLR9 has been shown to be protected from the disease, indicating a role of nucleic acid sensing in the innate initiation of the pathology (Miura et al. 2010). However, TLR9 expression in mice is not restricted to pDCs and B cells as in humans and thus a role of pDCs cannot be ascertained from this data only. Mitochondrial DNA released by hepatocytes has been implicated for TLR9 activation in another study (Garcia-Martinez et al. 2016). Another study though demonstrated STING activation in Kupffer cells in response to mitochondrial DNA, which also can drive a type I IFN response alongside proinflammatory cytokine induction, viz. IL-1β (Luo et al. 2018; Yu et al. 2019). Interestingly, a role of TLR7 activation has also proposed to contribute to NASH in preclinical model (Roh et al. 2018). The nature of involvement of type I IFNs in NASH too is yet to be understood fully. In preclinical models type I IFNs have been shown to play a protective role in the hepatic disease (Petrasek et al. 2011a, b). On the other hand, in another more recent study type I IFNs were found to drive T cell activation and thus fuel inflammation in liver (Ghazarian et al. 2017). In a more recent study it was found that ablating type I IFN signaling in specific cell types affected the disease differently (Wieser et al. 2018). This study reported that hepatocyte-specific ablation of type I IFN receptor worsened hepatosteatosis in methionine-choline deficient diet fed preclinical model of NASH, while adipocyte-specific ablation did not affect it. On the other hand, adipocyte-specific ablation of the receptor in HFD-fed obese mice worsened insulin resistance and weight gain. Hepatocyte-specific deletion did not have any effect in HFD-fed mice. Receptor ablation in myeloid cells or in intestinal epithelial cells did not have any effect in either model. Thus it seems that the role of

6.5

A Potential Pathogenic Continuum for Autoimmune Diseases and. . .

113

type I IFNs is multiprong and varied in outcome based on the cell subset experiencing IFN signaling and perhaps also the stage of the disease. The role of pDC as an important source of type I IFNs is far from clear. Nevertheless, in the HFD-fed preclinical model of metabolic syndrome associated with obesity it was found that there was striking recruitment of pDCs in the diseased mice. Absence of pDCs, due to DC-specific ablation of E2-2, protected fatty liver disease as well as insulin resistance (Hannibal et al. 2017). The same study also reported that a global absence of type I IFN receptor also protected the mice from metabolic disorders. Thus, role of pDCs and type I IFNs in NAFLD still remains an open question and an active area of research.

6.5

A Potential Pathogenic Continuum for Autoimmune Diseases and Metabolic Syndrome

As we revisit the role of pDCs and pDC-derived type I IFNs in different systemic autoimmune diseases, as discussed in the last chapter, as well as in variably in different components of metabolic syndrome described in the current chapter, a shared innate initiation of the chronic inflammation in these varied contexts becomes very apparent. The sequence of this putative shared pathogenetic event begins with recruitment and in situ activation of pDCs in response to endosomal TLRs being stimulated by self-origin nucleic acid molecules bound to different endogenous danger molecules, viz. HMGB1 and LL37, as well as immune complexes. The immunocellular events downstream of type I IFN induction by pDCs are variably comprised of activation of macrophages, epithelial and endothelial dysfunction, T cell activation, and expansion of autoreactive B cells (Fig. 6.3). Of note here, clinical and epidemiological data on concurrence of metabolic disorders in different autoimmune diseases are quite abundant (Pereira et al. 2009). Concurrent insulin resistance and even a predilection for cardiovascular events in patients with type 1 diabetes mellitus is established (Teupe and Bergis 1991; Orchard et al. 2003; Kilpatrick et al. 2007). Patients with systemic lupus erythematosus (SLE) are shown to be more prone to development of atherosclerosis (Manzi et al. 1997; Roman et al. 2003). This predilection is also reiterated in a murine preclinical model of SLE (Ryan et al. 2006; Vilà et al. 2012). Patients affected with psoriasis too have been shown to be more prone to development of insulin resistance as well as adverse cardiovascular inflictions (Armstrong et al. 2015; Ogdie et al. 2015). Rheumatoid arthritis (RA) patients are known to be predisposed to metabolic derangements and atherosclerosis (Ku et al. 2009; Müller et al. 2017). Even patients with Sjogren syndrome (SS) and systemic sclerosis (SSc) have also been shown to have a predilection toward metabolic disorders and atherosclerosis (Ramos-Casals et al. 2007; Bartoloni et al. 2015; Ngian et al. 2012; Soriano et al. 2014). Finally, concurrent as well as sequential clinical presentations

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Fig. 6.3 Clinical concurrence of different systemic autoimmunities and metabolic disorders. The documented concurrence of systemic autoimmunities, viz. systemic lupus, psoriasis, rheumatoid arthritis, Sjogren syndrome, type 1 diabetes and systemic sclerosis, and different components of metabolic syndrome, viz. insulin resistance and atherosclerotic disease, has been shown. (Image by Dipyaman Ganguly, 2022)

among different autoimmune diseases is well appreciated, viz. in patients with SLE, RA, psoriasis, SS, and SSc, which may be in terms of sharing of autoantigens as well as inflammatory involvement of characteristic tissues (Alarcón-Segovia et al. 2005; Amador-Patarroyo et al. 2012; Rojas-Villarraga et al. 2012). Thus in terms of concurrence of pathologies too suggestion of a shared underlying mechanism gains ground (Fig. 6.4). The data from various studies done in these different clinical contexts point to a possible role of pDCs and pDC-derived type I IFNs as a shared innate immune event (Ganguly 2018). This is well established in case of the different autoimmune diseases (Higgs et al. 2011; Ganguly 2018). In case of different components of metabolic syndrome also a role of type I IFNs, and possibly also of pDCs as the major producers of these cytokines, is gradually being apparent. Whether this sharing of pathogenetic events belong to a pathogenic continuum and actually justifies a syndromic description for all these discreet clinical contexts warrants further validation and contemplation.

References

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Fig. 6.4 Secondary immunocellular events and tissue responses to type I interferon induction by plasmacytoid dendritic cells. Type I interferon induction by plasmacytoid dendritic cells links the event of aberrant extracellular release of nuclear antigens with a plethora of secondary immunocellular activation events, viz. proinflammatory polarization of macrophages, priming and expansion of autoreactive T cells and B cells. These immunocellular events, in isolation or in combination depending on the specific contexts, may drive several discreet tissue-based outcomes. (Reproduced with permission from Ganguly D, 2018)

6.6

Conclusions

More recent studies in different clinical contexts of metabolic disorders as well as in preclinical models of the relevant diseases are revealing an important role of pDCs and pDC-derived type I IFNs being played within the chronic low grade inflammation that is encountered systemically as well as in the metabolic tissues. Among the major components of metabolic syndrome pathogenesis of obesity and associated insulin resistance as well as atherosclerosis have been shown to have crucial contributions from pDC-derived type I IFNs. Role of pDCs and type I IFNs in hepatic metaflammation is still not understood fully. Finally, the shared pathogenetic event involving pDC activation and type I IFN induction in different autoimmune diseases and different components of metabolic syndrome, as well as the clinical evidence of frequent concurrence of these apparently distinct pathologies, point to the possibility of a pathogenic continuum that warrants further exploration.

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Chapter 7

Tolerogenic Functions of Plasmacytoid Dendritic Cells

Dendritic cells in the steady state circulate throughout the body, home to tissues, sample antigens, migrate to draining lymph nodes through high endothelial venules, interact with the T cells, present processed antigen as peptides bound on MHC molecules (pMHC) which bind to cognate T cell receptors (TCRs) driving activation of T cells and clonal expansion. When the antigen is encountered in the context of PRR (e.g., toll-like receptors or TLRs) activation the dendritic cells (this classical description is for the conventional dendritic cells or cDCs) also undergo maturation, in terms of expression of a plethora of activatory costimulatory molecules, viz. CD80, CD86, CD83, as well as production of proinflammatory cytokines, viz. IL-12, TNF-α, IL-6, etc. When the DC costimulatory molecules engage their cognate receptors on the T cells (so-called signal-2) while the pMHC engages the TCRs (the signal-1) and the local milieu is abundant with proinflammatory cytokines (the signal-3), an effective T cell activation ensues and clonal expansion of T cells happen. In the absence of signal-2 or 3 cDCs have been described to assume a tolerogenic phenotype, driving either T cells anergy or promoting development of T cells producing immunoregulatory cytokines like IL-10 or T cells expressing FoxP3, which the bona fide Tr1 cells or Tregs respectively. Plasmacytoid dendritic cells (pDCs) predominantly express the endosomal TLRs TLR7 and TLR9, recognizing single stranded RNA (ssRNA) and double stranded DNA (dsDNA), potentially of both pathogenic and self-origin, and drive a rapid and robust type I IFN induction locally in response to these ligands (Kadowaki et al. 2001; Hornung et al. 2002; Gilliet et al. 2008; Reizis et al. 2011). Although expression of few other surface TLRs that can recognize bacterial molecules have also been reported in human pDCs by some studies (Raieli et al. 2019). Moreover, PDCs adopt a sentinel function like cDCs as well and similar migration of pDCs to lymph nodes following antigen sampling and maturation have been documented (Yoneyama et al. 2004; Matsutani et al. 2007). Both in the steady state tissue, as well as while a tissue is inflamed, tissue-recruited pDCs express CCR7 and migrate to lymph nodes (Seth et al. 2011). Thus very similar to cDCs, a tolerogenic potential of pDCs, visiting lymph nodes and driving tolerance in T cells, should be anticipated, © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 D. Ganguly, Plasmacytoid Dendritic Cells, https://doi.org/10.1007/978-981-19-5595-2_7

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which has been demonstrated in experimental studies as well. But as the ability to sample diverse antigens, respond to diverse pathogen ligands and MHC-II-restricted antigen presentation ability of the cDCs are far more potent than pDCs, for peripheral induction of tolerance in T cells, for example, induction of IL-10-producing Tr1 cells and FoxP3-expressing induced Tregs (iTregs) cDCs should be physiologically better suited. Nevertheless, the specific contexts, especially in terms of specific tissues and clinico-pathologic contexts, wherein tolerogenic role of pDCs are well documented, will be discussed in this chapter.

7.1

Thymic pDCs and Central Tolerance

A major subset of circulating Foxp3+ Tregs are generated in the thymus, bearing specificities for especially self-antigens, known as the natural Tregs or nTregs. The nTregs are an important component of the so-called central tolerance for selfantigens, apart from the negative selection of self-reactive T cells that show very high affinity to the self-peptide-MHC complexes presented on thymic epithelial cells (TECs). The nTregs come into the periphery and interfere with effector function of self-reactive T cell clones by a suppressive activity mediated by both surface receptors and cytokines like IL-10 and TGF-β. Indeed, the TCR repertoire of the thymic nTregs and peripherally induced iTregs have been shown to be distinct, nTregs bearing TCRs recognizing self-antigens, while iTregs with TCRs with affinity for non-self-antigens as well (Wyss et al. 2016). The antigen presentation function by the thymus-resident cDCs has been shown to contribute to nTreg generation in the thymus, other than TECs (Fontenot and Rudensky 2005). It has been shown that the cytokine thymic stromal lymphopoietin (TSLP) released by the TECs present in the Hassal’s corpuscles of human thymic medulla acts on thymic cDCs and these cDCs drive development of nTregs from the positively selected CD4+ CD8+ T cells, by a secondary selection of medium to highaffinity self-antigen-specific TCR-bearing Tregs (Watanabe et al. 2005). PDCs in the human thymic medulla also express receptors for TSLP and just like cDCs they can drive nTreg generation (Hanabuchi et al. 2010). Another study has proposed a major role of CD40-CD40L interaction between thymic pDCs and T cells in this nTreggenerating function of pDCs as well (Martín-Gayo et al. 2010). Thus pDCs play a major role in the central tolerance against self-antigens through nTreg generation. Interestingly, distinct functional phenotypes of the nTregs, generated by the antigene presenting cells (APCs), viz. cDCs and pDCs, have been described. The Foxp3+ nTregs generated through interaction with thymic pDCs produce more IL-10 and much less TGF-β, compared to the ones generated by cDCs (Young et al. 2008; Hanabuchi et al. 2010). Notably, at least two major subsets of Foxp3+ Tregs have been described among both the centrally generated (thymic) nTregs and the peripherally induced iTregs, based on expression of the costimulatory molecule named Inducible Costimulator (ICOS). It has been shown that at least in humans ICOS+ Tregs are more potent

7.2

Mucosal Tolerance Driven by pDCs

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IL-10 inducers compared to the ICOS- Tregs (Ito et al. 2008). The IL-10 released by the ICOS+ Tregs can suppress cDC activation while TGF-β released by them exert suppression on effector T cells. The ICOS- Tregs produce predominantly TGF-β. Whether this functional diversification is instructed by the APCs involved in their generation is not very clearly understood. Nevertheless, human pDCs do express the ligand for ICOS (ICOSL) and ICOSL-ICOS interaction has been implicated in peripheral Treg generation by pDCs in different clinical contexts, especially cancer, which we will discuss in a later chapter (Conrad et al. 2012). Another phenotypic specialty about the nTregs is the stability of expression of FoxP3, the master transcription factor for Treg identity and suppressive function. In mice, while FoxP3 expression is stable in nTregs, it may undergo repression in iTregs in response specific inflammatory cues, generating an effector phenotype characterized by expression of the proinflammatory cytokine IL-17 (Komatsu et al. 2014; Yang et al. 2016). Whether stability of FoxP3 expression also depends on the nature of APCs the Tregs were generated by is an intriguing question. Thus, whether pDC-driven Treg generation, both in the thymus and in the periphery, affects FoxP3 stability is something that will be very important to know about to fully appreciate the role of pDCs in inducing Tregs and thus warrants further studies.

7.2

Mucosal Tolerance Driven by pDCs

The gastrointestinal mucosa encounters innumerable antigens that come from oral intake. The antigens are sampled by the mucosal DC subsets as well as other antigen presenting cells like macrophages. The antigens are presented to adaptive immune cells in the mucosa associated lymphoid structures (MALT), Peyer’s patches and in the draining mesenteric lymph nodes. A large abundance of antigen also reach the liver via the portal vein on being absorbed from the intestines and get presented within the liver. Moreover gut is the home for millions of microorganisms, including bacteria, viruses, fungi, and parasites, with a large fraction of them being commensals and integrated physiologically with the immunocellular representations in that tissue niche, the so-called gut microbiota. Antigens from these microorganisms are routinely samples, presented and reacted to, or immunologically ignored, based on immunocellular crosstalks operative in different tissue niches and gut-associated lymphoid tissues. As expected, apart from the sentinel function against potentially pathogenic antigenic sources, a dominant role of local immune tolerance ensures integrity of gut physiology. It has been shown that pDCs do populate the Peyer’s patches and the functional phenotype presented by the Peyer’s patch pDCs is distinct. PDCs isolated from murine Peyer’s patches were found to be deficient in terms of type I IFN induction in response to TLR activation. The mucosal factors that might be responsible for the functional derangement of the Peyer’s patch resident pDCs were proposed to be IL-10, TGF-β, and prostaglandin E2 released by the mucosal tissue (Contractor et al. 2007). One study reported a differential distribution of cDCs and pDCs in the gut,

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with pDCs dominating the lamina propria and Peyer’s patches and cDCs being more abundant in the mesenteric lymph nodes. This distribution may reflect an immune teleology of avoiding hyper-immune response against the commensal microbiota. Indeed, administration of a probiotic made with eight different commensal bacteria (Lactobacillus, Bifidobacterium, and Streptococcus strains) in mice led to a distinct change in the pDC abundance in the gut niches—a reduction in the lamina propria and strikingly high abundance in the lymph nodes (Wang et al. 2009). This points to the plausible role of gut microbial composition on differential DC distribution in different gut-associated lymphoid niches. Antigen exposure through oral route is known to induce tolerance. This is an important physiologic mechanism to prevent deleterious delayed-type hypersensitivity (DTH) reactions, driven by activated T cells, to exogenous antigens from both diet and the environment (Mowat 2003). Indeed, antigen feeding has been shown, both in humans and in experimental animals, to drive T cell tolerance to systemic exposure of antigens (Husby et al. 1994; Dubois et al. 2003). A critical role of Tregs has also been shown in mediating oral tolerance to the hapten 2.4dinitrofluorobenzene (DNFB), where in oral feeding prevented subsequent DTH reaction to DNFB exposure to skin (Dubois et al. 2003). Such tolerance induction by antigen feeding has been shown to be dependent on mesenteric lymph nodes, but not on Peyer’s patches, with gut DC subsets implicated for the antigen carriage and presentation to T cells in the lymph nodes (Spahn et al. 2001; Worbs et al. 2006), presumably driving antigen-specific Treg generation. The gut-resident CD103+ cDC subset has been implicated in this function (Matteoli et al. 2010; Païdassi et al. 2011). Interestingly, it is also known for long that gut venus drainage through the portal vein passing through liver parenchyma is also essential for oral tolerance to antigens (Cantor and Dumont 1967; Yang et al. 1994). It has been shown that a porto-caval anastomoses that shunts intestinal venous blood preventing it to go through liver prevents tolerance to orally fed antigens. Thus antigen presentation in the liver seems to play critical role in oral tolerance. In liver a large variety of cells can adopt the function of antigen presentation, including hepatic DC subsets (both cDCs and pDCs), Kupffer cells, macrophages, stellate cells, even the hepatocytes (Crispe 2011). Using the murine model, wherein oral tolerance induction by oral feeding of DNFB prevents subsequent DTH on skin exposure to DNFB, it was shown that pDCs in liver were responsible for the tolerogenic antigen presentation and Treg generation in response to DNFB after oral feeding (Goubier et al. 2008). Depletion of pDCs prevented oral tolerance to DNFB. This phenomenon was not restricted to the CD8 T cell-mediated DTH response. A CD4 T cell dependent DTH response to ovalbumin was also shown to get tolerized on prior gut exposure and this was also dependent upon hepatic pDCs. A role of Tregs was also associated with the tolerogenic function of pDCs (Dubois et al. 2009). Similar mucosal tolerance to antigen is also documented in airway mucosa and a role of pDC has been demonstrated. In response to innocuous inhaled antigens it has been shown that mucosal pDCs in the airways drive tolerance. A study found that in such cases both cDCs and pDCs internalize inhaled antigens in the lungs and present

7.3

Tolerogenic pDCs and Tissue Transplantation

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them to T cells in the draining lymph nodes. If inhalation of an inert antigen followed depletion of pDCs in mice, it leads to allergic response by helper type 2 T cell (Th2 cell) expansion, immunoglobulin E production, eosinophilia and goblet cell activation, creating an allergic asthma like phenotype (de Heer et al. 2004). It seemed that pDCs played the tolerogenic role in this setting through suppression of effector T cell priming by cDCs, which may be due to generation of iTregs in situ. Of note here in majority of real life clinical contexts airway hyper-reactivity and asthma are associated with or exacerbated by viral infections. As pDC-derived type I IFNs are critical mediators of anti-viral immunity, both type I IFN production as well as tolerogenic function by pDCs may play their role in vivo. Notably, circulating pDC frequency has been found to be linked inversely with respiratory infections in neonates, presumably due to the type I IFN inducing function of pDCs (Upham et al. 2009). On the other hand, deficiency of pDCs in neonatal mice increases their susceptibility to allergic airway inflammation in an experimental asthma model. When pDCs were adoptively transferred, or with administration of IFN-α, the severity of the allergic inflammation could be abated (Wu et al. 2020). This was also found in adult mice and this protective function of pDCs was not found to be mediated by Treg generation, rather presumably occurred due to IFN-α-mediated inhibition of lung epithelial cell-derived chemokines responsible for recruiting type 2 cDCs and type 2 innate lymphoid cells (ILC2). In another study in a model of respiratory syncytial virus induced bronchiolitis it was found that deficiency of pDC (achieved by using the BDCA2-DTR transgene in mice responding to diphtheria toxin) aggravated the disease severity and the antiinflammatory effect of pDCs in this context was mediated by Treg expansion in the lungs (Lynch et al. 2018). Thus in the airway mucosa the role of pDCs either through protective Th1 immune response through type I IFN induction or through tolerance induced by Treg expansion, is diverse and contextually determined. It was more evident in a recent study that reported that eosinophils prevented type I IFN induction in pDCs in response to viruses (Dill-McFarland et al. 2022). Thus in the airway mucosa the allergic inflammation and viral infection can together conjure up a complex cross-regulation of immune cells like pDCs and instruct the eventual effect of these cells in the inflammatory process.

7.3

Tolerogenic pDCs and Tissue Transplantation

Potential role of pDCs as tolerogenic cells in the context of tissue transplantation came from experiments with allogeneic bone marrow, containing hematopoietic stem cells (HSCs), transplantation in mice. It was found that HSCs engraftment was optimal and graft versus host disease (GVHD) was prevented in the presence of the so-called facilitating cells which were identified to be pDCs (Fugier-Vivier et al. 2005). In patients receiving allogeneic stem cell transplantation a lower abundance of circulating pDCs has been associated with early mortality too (Gonçalves et al. 2015). In several preclinical studies GVHD-promoting effect of pDC depletion from

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BM grafts and GVHD mitigating effect by reconstitution of pDCs and inhibition of effector T cells have been demonstrated (Banovic et al. 2009; Li et al. 2009; Lu et al. 2012). Several cytokines and growth factors are variably used for HSC mobilization prior to transplantation. Among them G-CSF and Plerixafor (an inhibitor for CXCR4/CXCL12 or stromal cell-derived factor 1α that helps HSC to emigrate bone marrow niche) have been clinically used, while FLT3L has been tried in a lot of preclinical studies (Uy et al. 2012; Saraceni et al. 2015). It has been shown that FLT3L and plerixafor alone or in combination prevent GVHD to a great extent, possibly due to their action on pDC and Treg mobilization, respectively (He et al. 2014). A role of the chemokine receptor CCR9 has been implicated in modulating the tolerogenic potential of pDCs. CCR9 is known to be homing receptor (responding to the chemokine CCL25) for pDCs which drive them to the small intestine (Wendland et al. 2007). CCR9+ pDCs were found to be of immature phenotype in one study, on activation with TLR ligands CCR9 expression went down. CCR9+ pDCs were efficient in driving Treg expansion and was able to prevent GVHD in a preclinical model (Hadeiba et al. 2008). On the contrary, in some contexts of tissue-specific acute GVHD a detrimental proinflammatory role of pDC has also been demonstrated. In case of gastrointestinal acute GVHD pDC mobilization and IFN-α production have been associated with IL-17 production from effector T cells driving inflammation (Bossard et al. 2012). Whether in this context a CCR9- but gut-homing pDC subset are implicated is not known, and thus remains an open question. In the context of allogeneic cardiac transplantation too it was found that a single preoperative infusion of hosts with bone marrow-derived (FLT3L-expanded) pDCs led to increase in allogeneic cardiac graft survival (Abe et al. 2005). Interestingly, it was found that this tolerogenic effect was not allo-antigen-specific as pDCs from a third allo-strain also could achieve similar prolongation of graft survival. Similar tolerogenic function was also demonstrated in case of FLT3L-mobilized splenic pDCs as well (Björck et al. 2005). In a subsequent study, again with vascularized cardiac allografts, it was shown that pDCs sampled antigens from the allograft, presented the antigen to T cell in the draining lymph nodes and promoted expansion of antigen-specific CCR4+ FoxP3+ Tregs (Ochando et al. 2006). Depletion of pDC or inhibiting lymph node homing of the pDCs prevented Treg generation and graft tolerance. Interestingly, in a rat model of cardiac allograft pDC homing to lymph node was not found necessary. PDCs homed to the graft and spleen and drove CD8+ Treg expansion (Li et al. 2010). It was found in this study that pDCs also thwarted CD4 T cell activation directly employing indolamine-2,3-dioxygenase (IDO), apart from generation of the CD8+ Tregs. IDO functions in pDC, like in other cells, to rewire the tryptophan metabolism pathway producing immune regulatory metabolites like kynurenine (Fallarino et al. 2007), as will be discussed later too in the context of cancers. In a recent study pDC-driven expansion of Treg cells have been demonstrated directly to be critical for achieving tolerance in a model of allogeneic cardiac

7.5

Conclusions

127

transplantation (Fu et al. 2021). The immunosuppression was achieved in this case by inhibiting mTOR using rapamycin and blocking the chemokine receptor CXCR4 using plerixafor (a small molecule antagonist for CXCR4), which reduced T cell infiltration and a markedly higher abundance of Treg cells, leading to prolonged graft survival. Bone marrow homing of both, Treg cells and DCs, has been shown to depend on CXCR4/SDF1α interaction (Zou et al. 2004; Nakano et al. 2017). Interestingly, plerixafor treatment in this allo-transplantation model was also associated with a significant mobilization of pDCs. More importantly, in the absence of pDCs (depleted by a monoclonal antibody) the immunosuppression failed reducing the graft survival significantly. In human patients receiving liver allo-transplants it was reported that circulating pDC abundance was associated with tolerant pediatric recipients as well as successful withdrawal of immunosuppression in adult recipients (Mazariegos et al. 2003, 2005). It was reported that in the tolerant transplant recipients there was a correlation of the circulating FoxP3+ Tregs with the ratio of PDL-1/CD86 on circulating pDCs (Tokita et al. 2008), which was intuitively explicable given the role of PDL1-PD1 interaction as an inhibitory immune checkpoint on T cells, as opposed to CD86.

7.4

Suppression of Anti-cancer Immunity

A major outcome of the tolerogenic potential of pDCs is their pro-cancer role. As we will discuss in a subsequent chapter of this volume, pDC recruitment into tumor bed has been associated with attenuation of anti-cancer immune mechanisms and these intra-tumoral pDCs are usually rendered deficient in terms of type I IFN induction in response to TLR stimulation. The tolerogenic functions are mediated to great extent by expansion of Tregs, which will be discussed in a greater detail in the chapter on role of pDCs in cancer.

7.5

Conclusions

PDCs are more often identified with its proinflammatory interferogenic functions, as the antigen presentation functions of pDCs are less conspicuous than that of the cDCs. However, pDCs are also known to play a major role in inducing tolerance through its antigen presentation function. On one hand pDCs have been shown to play a major role in central tolerance by driving generation of Tregs in the thymus. On the other hand tolerogenic functions of peripheral pDCs play crucial role in clinical contexts ranging from allergic inflammation to graft versus host disease. Deeper understanding of the tolerogenic functions of pDCs will enable designing novel immunotherapeutic strategies and identifying novel therapeutic targets in diverse clinical contexts.

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Chapter 8

Plasmacytoid Dendritic Cells and Cancer

In case of oncogenic transformation in any part of the body the immune system launches a concerted effort to prevent cancer growth and metastasis. In fact clinically apparent cancers may be taken as outcome of eventual immune escape of the concerned cancer cells, breaching the cancer immunosurveillance mechanisms (Dunn et al. 2004). As expected an inflammatory functional differentiation of the immune cell subsets help in anti-cancer immunity, while a functional differentiation toward tolerance helps oncogenesis. In cancers, especially in case of solid tumors, major cellular energy expenditure is thus devoted, apart from cellular growth and proliferation, to adopting mechanisms that drive a state of immunosuppression in the microenvironment. Being the professional type I interferon (IFNs) producers among the immune cells plasmacytoid dendritic cells are expected to have a major role in anti-cancer immune response. While exploring this rather a major role of pDCs in mediating immune evasion for cancers was also revealed. In this chapter we will discuss these counteracting functions of pDCs in the context of cancer.

8.1

Plasmacytoid Dendritic Cells and the “Cancer-immunity Cycle”

Anti-cancer immune response has been described as a “self-propagating” cycle, the so-called cancer-immunity cycle, divided in seven major events, viz. cancer cell death in the tumor and release of antigens, tumor antigen sampling by antigen presenting cells (APC) like dendritic cells (DC), antigen presentation and priming of lymphocytes in the draining lymph nodes, migration of the primed T cells toward the tumor, infiltration of T cells and natural killer (NK) cells into the tumor bed, recognition of tumor antigens and killing of cancer cells by the cytotoxic CD8 T cells and NK cells (Chen and Mellman 2013). Each of these steps comprises of mechanisms promoting anti-cancer immunity and in turn can be affected by regulatory © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 D. Ganguly, Plasmacytoid Dendritic Cells, https://doi.org/10.1007/978-981-19-5595-2_8

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mechanisms that suppress anti-cancer immunity, e.g. less immunogenic cancer cell death preventing release of tumor antigens, immunoregulatory cytokine milieu interfering with antigen sampling and activation of APCs, low co-stimulatory molecule expression by APCs (like CD80, CD86, CD83), and expression of immune checkpoint molecules (like PD1-PDL1, CTLA4-B7.1 interactions between APCs and T cells) preventing T cell priming, endothelial dysfunction inhibiting T cell infiltration into the tumor and finally reduced antigen presentation and immune checkpoint molecule expression by cancer cells preventing cytotoxic T cell function and inhibitory effect of regulatory T cells (Treg) and in situ differentiation of myeloid derived suppressor cells (MDSC) and immunosuppressive stromal cells (Ferguson et al. 2011; Mellman et al. 2011; Franciszkiewicz et al. 2012, 2013; Topalian et al. 2015). The major physiological functions of plasmacytoid dendritic cells (pDC) is rapid production of large amounts of type I interferons (type I IFN) in response to activation of its endosomal toll-like receptors (TLR), viz. TLR7 and TLR9, which recognize nucleic acid ligands of both self and non-self-origin, apart from their rather minor contribution in antigen presentation and T cell priming as well. Type I IFNs have the ability to potentiate multiple steps of the cancer-immunity cycle, including maturation of the antigen presenting cells, T cell priming, and T cell activation (Fig. 8.1). Thus pDCs have the potential for efficiently contribute to anti-cancer immunity and most cancers do exhibit a notable recruitment of pDCs in the tumor bed. But based on studies done in different contexts of human cancers, as we will discuss below, pDCs also appear to be very prone to various immunosuppressive mechanisms emerging in the tumor microenvironment.

8.2

Leukemogenesis and pDCs

Growth dysregulation following oncogenic transformation in hematopoietic pregenitors leads to leukemogenesis, causing leukemias of different blood cells. A rather immunoregulatory role of pDCs has been suggested in different contexts of leukemia (Zhou et al. 2021). In chronic myeloid leukemia islands of CD123+ pDCs have been demonstrated in the hematopoietic niche of the leukemogenic cells. For example, a recent study found greatly enriched pDC compartment in the bone marrow, expressing BDCA2, BDCA4, and HLA-DR, in almost 20% patients of chronic myelomonocytic leukemia (Lucas et al. 2019). More importantly, the CD34+ HSCs could differentiate into these cells in a FLT3L-independent manner and the abundance of these clonally expanded pDCs were associated with higher abundance of Tregs in bone marrow. Thus in this case, the myeloid oncogenic transformation perhaps also drive an expansion in the pDC compartment, which in turn gleans an immunoregulatory effect in favor of leukemogenesis. Hematopoietic dysregulations also lead to cancerous proliferation of the pDC compartment itself. For example, leukemogenesis affecting pDCs are known to cause a very rare form of leukemia named blastic plasmacytoid dendritic cell

8.3

Breast Cancer and pDCs

135

Fig. 8.1 Potential contribution of plasmacytoid dendritic cells in the cancer-immunity cycle. Type I interferon produced by plasmacytoid dendritic cells can promote several crucial steps in the cancer-immunity cycle, viz. immunogenic cell death of cancer cells, cancer antigen sampling by conventional dendritic cells, T cell priming by conventional dendritic cells, T cell activation as well as recognition and killing of cancer cells by cytotoxic T cells as well as NL cells (not showed). (Image by Dipyaman Ganguly, 2022)

neoplasm or BPDCN, usually in elderly males (Zhou et al. 2021). Interestingly, BPDCN is more frequent among males (at least three times). A recent study identified mutation in the gene ZRSR2 may underlie the sex-bias (Togami et al. 2022). ZRSR2 is a X chromosome gene and the mutations affect mostly males and functionally inhibits both activation and apoptosis of pDCs in the context of inflammation. On the other hand growth dysregulation is mature pDCs have been linked to subtypes of myeloid leukemia, e.g. recently one study identified a pDC-AML with cells showing no CD56, low CD123 but high expression of CD34 and BDCA2 (Zalmaï et al. 2021). This clonally expanded pDCs show the characteristic IFN induction in response to TLR stimulation.

8.3

Breast Cancer and pDCs

Breast cancer is the second most frequent cancer associated with cancer mortality among women worldwide (Fahad Ullah 2019). The disruption of the cancerimmunity cycle by immunoregulatory events within the tumor bed is very well

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documented in breast cancers. Likewise, studies conducted in breast cancer also offered insights discreet intra-tumoral mechanisms that render tumor-recruited pDCs dysfunctional and tolerogenic (Demoulin et al. 2013; Lombardi et al. 2015; Zhou et al. 2021). CD123+ pDC infiltration in breast cancer was found to be associated with worse prognosis in terms of relapse-free survival as well as overall survival (Treilleux et al. 2004). PDC infiltration is more in breast tumors with higher mitotic index as well as the more aggressive triple-negative cancers (expressing neither Her2/neu nor the hormone receptors for estrogen or progesterone) (Sisirak et al. 2012). Tumorinfiltrating pDCs lose the ability to produce type I IFNs in response to TLR activation as demonstrated in ex vivo studies (Sisirak et al. 2012; Raychaudhuri et al. 2019). The underlying mechanism for the inability for the intra-tumoral pDCs to efficiently mount a type I IFN response to TLR activation has been linked in one study to cancer cell-derived TGF-β and TNF-α (Sisirak et al. 2013). In recent study a potential role of an oncometabolite has been implicated. As usual with most cancer cells the cellular respiration undergoes a glycolytic switch resulting in increased production and release of lactate in the microenvironment, described as the Warburg effect (Warburg et al. 1927). The cancer cell-derived lactate has been shown to affect intra-tumoral pDCs by signaling through the lactate receptor GPR81, mobilizing intracellular Ca2+, which in turn inhibit type I IFN induction by pDCs (Raychaudhuri et al. 2019, 2020). The lactate receptors on pDC cell surface also import lactate and thereby reprogramming the pDC cellular respiration toward reduced glycolysis, which is a critical prerequisite for pDC activation as well (Wculek et al. 2019; Bajwa et al. 2016). Intra-tumoral pDCs have been shown to instruct differentiation of Tregs, which in turn further attenuates the anti-cancer immune response by disrupting the cancerimmunity cycle (Sisirak et al. 2012; Raychaudhuri et al. 2019). Interaction between ICOSL on pDCs and ICOS on T cells, driving Treg expansion, has been implicated in a study to be the major mechanism of immunosuppression in breast cancer (Gehrie et al. 2011; Faget et al. 2012). Thus ICOS-ICOSL interaction appears to be a potential anti-cancer immunotherapeutic target to circumvent the tolerogenic functions of intra-tumoral pDCs. Interestingly, in a recent study the breast tumor infiltrating pDCs were found to drive a very different immunoregulatory mechanism. Intra-tumoral pDCs was found to release kynurenine, a metabolite derived from a reprogrammed tryptophan metabolism in response to lactate (Raychaudhuri et al. 2019). Kynurenine signaling in T cells have previously been associated with Treg expansion in other contexts (Mezrich et al. 2010; Iannitti et al. 2013). Data showing a immunoregulatory role of an oncometabolite acting through intra-tumoral pDCs is intriguing and offers novel therapeutic targets. Therapeutic efficacy of targeting lactate receptors and transporters in pDCs in the context of solid tumors remains to be explored. Yet another study has reported a critical role of cancer cell-derived GM-CSF in driving pDC tolerance. Higher abundance of intra-tumoral GM-CSF and pDCs was associated with more aggressive cancers. GM-CSF signaling drove intra-tumoral

8.5

PDCs in Neoplasmas of the Aero-digestive Tract

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pDCs to drive differentiation of Th2 cells in situ, which attenuated the anti-cancer immune response (Ghirelli et al. 2015). PDC-derived TNF-α driving NFκB activation and CXCR4 expression in breast cancer cells has also been implicated in promoting spread to lymph nodes followed by distant metastasis (Gadalla et al. 2019). Whether these discreet regulatory events involving intra-tumoral pDCs in breast cancers co-operate with contextual skewing for one or the other in different stages of the disease, or with cancer cells of different mutational landscapes and epigenetic states, will be a very interesting domain for further research.

8.4

Ovarian Carcinoma and pDCs

PDCs infiltrating the tumor in ovarian cancer, the most aggressive cancer in women worldwide, has been also shown to be associated with poor prognosis (Labidi-Galy et al. 2011; Conrad et al. 2012). PDC recruitment to ovarian cancer was found to be guided by expression of CXCL12 by the cancer cells (Zou et al. 2001). CXCR4expressing pDCs upregulate the cell surface adhesion molecule VLA-5 and extravasated in the tumor bed. These pDCs are also protected from apoptosis in response to IL-10 released by intra-tumoral macrophages. The same study also demonstrated differentiation of IL-10-producing T cells by the tumor-recruited pDCs. Later, the tumor-recruited pDCs were demonstrated to drive Treg expansion through the interaction of ICOSL on pDCs and ICOSL expressed on T cells (Conrad et al. 2012). PDCs isolated from the ascites fluid collected from ovarian cancer patients, but not from blood, drove Foxp3+ Treg differentiation ex vivo. Inside the tumor pDCs and the ICOS+ Treg cells were found in close vicinity. Abundance of ICOS+ Tregs was correlated with that of intra-tumoral pDCs and these were strong predictors for progressive disease. In another study, CD123+ BDCA2+ pDCs were found to be the most numerous DCs in ovarian cancer tumor bed. There was a reduction of circulating pDCs in these patients, which increased following chemotherapy (Labidi-Galy et al. 2011). Interestingly, in this study the ascites fluid pDC abundance was not associated with poor prognosis, unlike intra-tumor pDC abundance, although pDCs isolated from ascites fluid drove IL-10 production in T cells ex vivo. A role of pDCs in driving regulatory phenotype in CD8 T cells is also described in ovarian cancer, which in turn drive the immunosuppressive function by producing IL-10, thereby rendering tumor-recruited effector T cells dysfunctional (Wei et al. 2005).

8.5

PDCs in Neoplasmas of the Aero-digestive Tract

Cancers in the oral cavity and neck region, other anatomical parts of the aerodigestive tract, pulmonary parenchyma and hepatic parenchyma comprise great fraction of cancer debility and mortality worldwide. PDC infiltration into the

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tumor bed in head and neck squamous cell cancers (HNSCC) and intra-tumoral dysfunction was reported decades ago (Hartmann et al. 2003). HNSCC cell supernatant renders pDCs unresponsive to TLR ligands and tumor-derived TGF-β and prostaglandin E2 had been implicated for this (Bekeredjian-Ding et al. 2009). Intratumoral abundance of pDCs in oral squamous cancers has been linked to disease progression and poor prognosis as well (Han et al. 2017). Further support comes from recent study showing that depletion of pDCs in an immunocompetent transgenic preclinical murine genetic model of HNSCC, using anti- CD317 monoclonal antibodies, leads to reduced abundance of intra-tumoral Tregs as well as MDSCs and a significant delay in tumor growth (Yang et al. 2019). Intra-tumoral functional diversification has also reported for pDCs in case of HNSCCs. For example, one study reported that intra-tumoral pDCs with CD56 expression have cytotoxic potential, although these cells are relatively few in the tumor microenvironment (Thiel et al. 2011). A recent study reported an increased expression of OX40 on a subset of intra-tumoral pDCs, which drive efficient anti-cancer immunity through their own cytolytic activity (through an autocrine OX40-OX40L interaction) as well as by promoting expansion of CD8 effector T cells (Poropatich et al. 2020). PDCs expressing OX40 were devoid of ICOSL expression, thus perhaps representing a dichotomous heterogeneity of intra-tumoral pDCs. Among the lung cancers in the non-small cell lung cancer (NSCLC) an enrichment of pDCs in the tumor bed has been documented by different groups, which is as usual linked to disease progression and unfavorable outcomes (Shi et al. 2014; Sorrentino et al. 2015). NSCLC-recruited pDCs have been also reported to have very low expression of costimulatory molecules like CD80 and CD86 and to be deficient in type I IFN induction in response to TLR stimulation (Perrot et al. 2007). Intra-tumoral pDCs in NSCLC also have been linked to expansion of Tregs, thereby affecting immunosuppression in situ (Sorrentino et al. 2010). Interestingly, PDL1expressing immunosuppressive pDCs in NSCLC was also shown to produce IL-1α, which promoted cancer cell proliferation (Sorrentino et al. 2015). In gastric cancer, the third highest contributor to cancer-related mortality globally, circulating and peritumoral pDC abundance has been linked to intra-tumoral ICOS+ Tregs as well as to disease progression and poor prognosis (Huang et al. 2014). A recent study reported correlative abundance of pDCs and Tregs in different micro-niches in gastric cancer patients, with higher intra-tumoral enrichment (Ling et al. 2019). Interestingly, these immune cells were also associated with specific microbiota enrichment in these micro-niches, which points to an intriguing crosstalk between tumor microenvironment and the tumor-proximal gastric microbial niches that are well known to contribute to oncogenesis and disease progression for gastric cancer in particular, and for gastrointestinal cancers in general (Grochowska et al. 2022; Kaźmierczak-Siedlecka et al. 2022; Nasr et al. 2020; Belkaid and Hand 2014). In case of liver cancers too, both in case of hepatocellular carcinoma and intrahepatic cholangiocarcinoma, intra-tumor pDC infiltration is associated with higher propensity for lymph node and distant metastases, and as a result linked to worse overall survival and high recurrence (Zhou et al. 2019; Hu et al. 2020). In both studies the characteristic association of Treg abundance was documented with intra-

8.6

Malignant Melanoma and pDCs

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tumoral pDCs. Another study on both primary hepatocellular carcinoma as well as hepatic metastases of colorectal cancers, reported intra-tumoral enrichment of Foxp3- IL-10-producing Tr1 cells, which correlated with intra-tumor abundance of pDCs (Pedroza-Gonzalez et al. 2015). In primary colorectal cancers also pDC recruitment into the tumors has been a predictor of clinical outcomes, but shows a dichotomous relationship (Kießler et al. 2021). Higher frequency of pDCs, especially when a major fraction of them were IRF7+ signifying an activated state, was correlated with higher activity of the effector CD8 T cells. On the other hand lower abundance pDC recruitment was linked independently to worse clinical outcomes, again signifying the possibility of functional heterogeneity of intra-tumoral pDCs and the contextual skewing of abundance. Interestingly, in a correlative analysis, innate lymphoid cell 3 (ILC3) abundance was found to be negatively correlated to intra-tumoral pDC abundance and linked to favorable clinical outcomes (Wu et al. 2021). In this study higher pDC abundance was linked to worse prognosis. This presumably contextual dichotomy is further elucidated in a recent study wherein it was shown that in neoadjuvant radiochemotherapy (NRCT) significantly influences the phenotype of intra-tumoral pDCs in rectal cancers (Wagner et al. 2019). NRCT increased the abundance of CD83+ activated pDCs in the tumor which produced type I IFNs and was linked to higher abundance of cytotoxic CD8+ T cells. A comparison between pre-NRCT and post-NRCT samples revealed that in pre-NRCT tumor pDCs produced less IFNs and expressed less CD83, thus representing a dysfunctional phenotype.

8.6

Malignant Melanoma and pDCs

A large number of studies into the role of pDCs in tumor microenvironment looked at malignant melanoma (MM). MM cells, both in humans as well as in its preclinical models in rodents, are immunogenic and thus growth and propagation is critically dependent on immune escape. So for exploring intra-tumoral immunoregulatory mechanisms this cancer has offered great insights. In MM patients there is striking recruitment of pDCs into the tumor (Jensen et al. 2012; Aspord et al. 2013), which is also reflected in a reduction in the circulating pDCS (Chevolet et al. 2015). A reduction in type I IFN induction in situ has also been linked to poor outcomes in MM (Vermi et al. 2003; Gerlini et al. 2007). For recruitment of pDCs into the tumor bed chemotactic cues like CCR9-CXCL12 and CCR6-CCL20 interactions have been implicated in different studies (Gerlini et al. 2007; Charles et al. 2010). It has been shown in MM that the tumor-recruited pDCs drove Th2 differentiation of CD4 T cells through OX40L and differentiation of IL-10 producing Tregs by ICOS-ICOSL interaction, two well-known mechanisms of immune regulation involving pDCs, which contributed to the tolerogenic microenvironment giving the tumors a growth advantage (Aspord et al. 2013). Expression of Indoleamine 2, 3-dioxygenase or IDO in pDCs has also been implicated in pDC-driven Treg expansion in draining lymph nodes (Gerlini et al. 2010). For the tolerogenic

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functional differentiation of tumor-recruited pDCs in MM, in one study a role of Wnt5a released by the cancer cells has been implicated (Hack et al. 2012). The tolerogenic mechanisms demonstrated for this in other cancers indubitably have the potential play critical roles in MM as well, e.g. production of immunoregulatory cytokines like IL-10, TGF-b by the cancer cells, and abundance of lactic acid in the tumor microenvironment, etc. (Monti et al. 2020a, b).

8.7

Conclusion

The studies in different contexts of human cancers reveal that the role of pDCs infiltrating the tumor bed in different cancers may be contextually determined. It seems pDCs are very prone to succumb to the intra-tumoral immunosuppressive microenvironment, losing its potential favorable effects on anti-cancer immunity. The deficiency in type I IFN induction in intra-tumoral pDCs is a more general snapshot which is documented, which may be secondary to different mechanisms operative in different contexts. As we discussed it can be from immunoregulatory cytokines released by cancer cells (like TGF-β and TNF-α) or the tumor-infiltrating myeloid cells (like IL-10) to the oncometabolite like lactate, which render intra-

Fig. 8.2 Functional dysregulation and tolerogenic effects of intra-tumoral plasmacytoid dendritic cells. Tumor-infiltrating plasmacytoid dendritic cells are rendered deficient in type I interferon induction by mediators released by the cancer cells, viz. TNF-α, TGF-β, and lactic acid. Rather a tolerogenic phenotype of the plasmacytoid dendritic cells ensues that promote expansion of T regulatory cell expansion by ICOS-ICOSL interaction or due to induction of indoleamine 2,3-dioxygenase (IDO) that produces anti-inflammatory metabolites. Effector T cells are also inhibited through PD1-PDL1 interactions driven by plasmacytoid dendritic cells. (Image by Dipyaman Ganguly, 2022)

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tumoral pDCs dysfunctional in aggressive tumors (Fig. 8.2). These functionally dysfunctional pDCs in turn drive tolerogenic Treg cells and Tr1 cells to further hinder an effective anti-cancer immunity. But as described earlier, pDC-derived type I IFNs have the potential to promote different critical events in the “cancer-immunity cycle,” ranging from potentiating antigen presentation to activating NK cells, polarizing a Th1 response and expanding cytotoxic CD8 T cells. Thus in contexts where function of pDCs to induce a local type I IFN response remains intact, or is protected or bolstered, pDCs assume the role of a favorable immune cell for anti-cancer immunity. Thus strategies to protect and bolster the function of intra-tumoral pDCs, appropriately designed for specific contexts, are extremely potential immunotherapeutic options in the context of cancers.

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Chapter 9

Therapeutic Targeting of Plasmacytoid Dendritic Cells

Diverse role of plasmacytoid dendritic cells (pDCs) as a key player in the pathogenesis of human diseases make them important targets of therapy. Pathogenetic roles of pDCs range from innate initiation of inflammation in autoreactive inflammation to orchestration of anti-viral immunity as well as assuming a pro-tumor tolerogenic phenotype in the context of cancer (Bencze et al. 2021). Thus therapeutic targeting in these different clinical contexts also must adopt diverse strategies and discreet targets in pDCs to achieve the intended clinical effects (Fig. 9.1). The major therapeutic strategies involving pDCs employ inhibition or enhancement of their activation phenotype by either targeting the endosomal toll-like receptors (TLRs) or the immunoregulatory molecules expressed by pDCs. These discreet strategies and the preclinical and clinical data associated with it are discussed in this chapter categorizing them according to the clinical contexts and the immunobiology involved in such contexts.

9.1 9.1.1

Targeting pDCs and Type I IFNs in Autoreactive Inflammation Targeting Endosomal TLRs in pDCs

As we learnt, endosomal TLR activation in pDCs in response to endogenous ligands and type I IFN induction is a shared innate initiation event in myriad clinical contexts of autoreactive inflammation and autoimmunity, viz. systemic lupus, psoriasis, Sjogren syndrome, systemic sclerosis, rheumatoid arthritis, type 1 diabetes as well as metabolic tissue inflammation in different metabolic disorders (Ganguly et al. 2013, 2018). Hydroxychloroquine (HCQ) is an anti-malarial drug. Modulation of endolysosomal acidification is implicated in the anti-malarial as well as anti-viral © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 D. Ganguly, Plasmacytoid Dendritic Cells, https://doi.org/10.1007/978-981-19-5595-2_9

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Fig. 9.1 Diverse contextualized strategies for therapeutic targeting of plasmacytoid dendritic cells. Pathogenic role of plasmacytoid dendritic cells vary in different clinical contexts, viz. driving autoreactive inflammation in autoimmune diseases, promotion of anti-viral immunity, driving a pro-tumor tolerogenic response in cancer. Therapeutic targeting in these different clinical contexts also adopt appropriately diverse strategies to achieve the intended clinical outcomes, viz. depletion of plasmacytoid dendritic cells using monoclonal antibodies, systemic blockade of type I interferon response or targeting endosomal toll-like receptors to inhibit type I interferon induction in autoimmune diseases, on the other hand driving toll-like receptor activation or generating pDC-based vaccines in the context of cancer. (Reproduced with permission from Bencze D et al., 2021)

activity of this drug (Sperber et al. 1993). Interestingly, hydroxychloroquine also affects acidification of the endosomal compartments in pDCs and thus inhibits endosomal TLR activation and type I IFN induction (Kuznik et al. 2011). Thus this drug has been used widely, not only as a small molecule inhibitor for mechanistic studies in pDCs, but also as a first line pharmacotherapy in a number of rheumatological diseases, viz. RA, SLE, and SS (Dörner 2010; CostedoatChalumeau et al. 2013; O’Dell et al. 2002; Morand et al. 1992; Sun et al. 2007; Gottenberg et al. 2014). Although the clinical use of the anti-malarial in rheumatological disorders predates full elucidation of its action (Lanham and Hughes 1982; McCarty and Carrera 1982). Interestingly, a recent study has found that the inhibitory effect of HCQ on endosomal TLR activation, at least in case of TLR7, may involve more than just increasing endosomal pH (Cenac et al. 2022). It has been found that this drug can

9.1

Targeting pDCs and Type I IFNs in Autoreactive Inflammation

149

prevent cleavage of TLR7 protein in human pDCs and accumulation of the full length TLR in the endosomes, leading to dysfunction. This was demonstrated to inhibit type I IFN induction both in response to synthetic TLR7 ligands and RNA viruses. Development of more specific agents to inhibit endosomal TLRs in pDCs has also been put a lot of efforts by different groups. These include both synthetic oligonucleotides that bind to the TLRs as well as small molecule inhibitors designed to inhibit TLR activation in pDCs (Kanzler et al. 2007; Barrat and Coffman 2008; Hennessy et al. 2010; Talukdar et al. 2021). The inhibitory oligonucleotides have shown promising data in preclinical models of different autoimmune contexts and some of them have also been taken to clinical trials. Mammalian telomeric sequences are not present in microorganismal genome. Based on these sequences a set of inhibitory oligonucleotides were developed which could inhibit TLR9 (Lenert 2006, 2010). These sequences were also shown to ameliorate disease in a preclinical mouse model of arthritis as well as a spontaneous model of systemic lupus in mice (Dong et al. 2004, 2005). In another study G-rich inhibitory oligonucleotides, that inhibit TLR9, were shown to ameliorate disease in the MRL/Lpr SLE model (Patole et al. 2005). Similar oligonucleotides with dual antagonism against TLR7 and TLR9 were also very efficient to ameliorate disease in the spontaneous mouse model of lupus as well as in a model for autoimmune skin inflammation (Barrat et al. 2007; Guiducci et al. 2010). Several of such inhibitory oligonucleotides have entered clinical trials, preliminary data has though been variable. With detailed structural information on human endosomal TLRs being available in last few years a more directed effort has been possible for rational design of small molecules. Several chemical scaffolds have been explored to rationally develop antagonists for endosomal TLRs, guided by their projected receptor binding. Orally bioavailable TLR9 and TLR7 antagonists have been reported by a group, based on quinazoline and purine scaffolds, that were demonstrated to inhibit human TLR7 and TLR9, with variable specificity among the two targets, in human primary pDCs, TLR9 reporter cells as well as in an in vivo mouse model showing activity against mouse endosomal TLRs as well (Paul et al. 2018; Mukherjee et al. 2020; Kundu et al. 2021). In the in vivo model the orally administered antagonists could inhibit systemic and local IFN-α induction in response to intraperitoneal injection with TLR9 ligands. A purine TLR7 antagonist, developed based on a agonist-to-antagonist conversion rationale based on purine agonists like imiquimod and resiquimod, was shown to prevent disease in a preclinical mouse model of psoriasis (Mukherjee et al. 2020). Interestingly, the antagonists were proposed to bind very close to the ligand binding area of these TLRs and a shared structural basis for the antagonistic activity has also been suggested that apply irrespective of the chemical scaffolds (Pal et al. 2021; Talukdar et al. 2021). The proposed interaction of these different small molecule antagonists of TLR9 and TLR7 with different clinical structure is shown in Fig. 9.2, which helps to appreciate the shared receptor targeting pattern. Further preclinical and clinical validation of such small molecule antagonists will validate their clinical applications.

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Fig. 9.2 Rationale for targeting endosomal toll-like receptors in plasmacytoid dendritic cells using small molecules. The figure summarizes the protein structure of the ligand binding domain of TLR7 dimer, with its representative reported antagonist molecules of diverse chemotypes (left panel) and that of TLR9 (right panel). The green and red dashed boxes indicate the antagonist binding site of TLR7 and TLR9, respectively. The interaction of a couple of antagonist molecules with specific amino acids in TLR7 (left) and TLR9 (right) are shown in the bottom, where green, magenta, and black dashed lines represent H-bonds, pi–pi interactions, and salt bridge, respectively. (Image by Uddipta Ghoshdastidar and Arindam Talukdar (CSIR-Indian Institute of Chemical Biology, India), 2022, used with permission)

9.2

Targeting pDCs in Infection

9.1.2

151

Biologics Targeting pDCs and Type I IFNs

Another widely explored approach to target pDCs and pDC-derived type I IFNs has been use of monoclonal antibodies. Both these approaches have been shown to efficacious in ameliorating autoreactive inflammation in different preclinical models in mice, wherein pDCs are targeted for depletion through antibody mediated cytotoxicity by using a monoclonal antibody against the pDC surface molecule mPDCA1 and systemic blockade of type I FN signaling is achieved using an antibody against the type I IFN receptor IFNAR1 (Rajagopal et al. 2010; Sheehan et al. 2006). Both these approaches are being explored in clinical trials in humans. Monoclonal antibodies against IFN-α (sifalimumab) as well as the type I IFN receptor (anifrolumab) have been tried in patients with systemic lupus erythematosus (SLE) with variable outcomes data (Khamashta et al. 2016; Koh et al. 2020). Among these clinical trial outcomes using anifrolumab has been very promising in SLE leading to recent FDA approval (Morand et al. 2020; Jayne et al. 2022; Vital et al. 2022). Several clinical trials are also ongoing using pDC-depleting monoclonal antibodies. A monoclonal antibody targeting BDCA2, named BIIB059, has shown to be safe and able to reduce systemic type I IFN induction and ameliorate skin lesions in patients with SLE (Furie et al. 2019). Another monoclonal antibody that targets ILT7 in human pDCs, named VIB7734, was shown to be efficacious in depleting circulating as well as lesional pDCs in patients with cutaneous lupus with considerable favorable outcome in terms of both safety and disease amelioration (Karnell et al. 2021).

9.2

Targeting pDCs in Infection

PDC-derived type I IFNs being the keystone of protective immunity against viral infections, and a critical participant in immune response against other infectious agents as well, targeting pDCs, especially the endosomal TLRs, has been a widely explored experimental strategy. Agonists of endosomal TLRs have been explored for both as therapeutic agents and as vaccine adjuvants. IFN-α has been in clinical use for a number of viral infections, especially hepatitis C virus (HCV), either alone or in combination with anti-viral drugs (Iino et al. 1994). Although improved anti-virals have been replacing its wide use, ways to activate endogenous type I IFN induction is still a potential anti-viral strategy and toward this targeting endosomal TLRs in pDCs is a widely tried strategy. The small molecule TLR7 agonist resiquimod has been through clinical trials in patients with herpesvirus (HSV2) infection as well as in HCV infections (Mark et al. 2007; Pockros et al. 2007). Both topical (in case of HSV2) and oral administration (for HCV) of resiquimod have been used with variable clinical outcomes warranting further studies. Imiquimod, another small molecule TLR7 agonist has also been in clinical

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use in HSV infections (Perkins et al. 2011). Another small molecule TLR7 agonist, ANA773, has also tried in chronic HCV patients with promising preliminary data in terms of dose-dependent reduction in viral titer, which seemed to be mediated through induction of type I IFNs in the body (Bergmann et al. 2011; Boonstra et al. 2012). Similarly, agonists of TLR9 have also been explored in clinical trials in patients with HCV and HBV infections, viz. the synthetic oligonucleotide IMO-2125, SD-101, and ISS1018, either alone or with viral antigen (Barry and Cooper 2007; Harandi et al. 2009). CpG-7909, another oligonucleotides TLR9 agonist, is also being explored in infections with bacillus anthracis as a vaccine adjuvant (Dorn and Kippenberger 2008). New adjuvant small molecules, designed to target endosomal TLRs, are also being actively pursued by several groups (Nuhn et al. 2018; Talukdar et al. 2021). A small molecule dual agonist for TLR7 and TLR8, attached to scaffolds that preferentially get enriched in the lymph nodes, has recently been successfully used as adjuvant with subunit vaccines against influenza and SAR-CoV-2 virus infection in a preclinical model (Jangra et al. 2021). Interestingly, Gen2.2 cells, a pDC cell line developed from a Blastic plasmacytoid dendritic cell neoplasm and widely used for a mechanistic studies, has been used in a study for ex vivo loading with antigens from hepatitis B virus followed by adoptively transfer in humanized mouse model (Martinet et al. 2012). This pDC-vaccine was shown to stimulate considerable anti-viral immune response.

9.3 9.3.1

Targeting pDCs in Cancer Targeting Endosomal TLRs and Other pDC-intrinsic Molecules

As we discussed before, in the context of cancer pDCs play clinically relevant tolerogenic role and fail in their proinflammatory functions, like type I IFN induction. A lot of effort has been put to devise strategies to evade this intra-tumoral pDC dysfunction and tolerogenicity, for example, by using TLR-agonists or by targeting pDC-specific molecules, a few among which we can discuss here to appreciate the potential of such strategies. In a melanoma preclinical model in humanized mice application of the TLR7 agonist imiquimod was shown to reinvigorate pDCs in producing type I IFNs, ramp up their cytotoxic functions, and as a result lead to tumor regression (Aspord et al. 2014). In human patients with melanoma a similar strategy of activating TLRs in pDCs have been tried using intradermal injection of CpGB, which was shown to activate pDCs in the sentinel lymph nodes driving induction of IFN-α in situ, expanding a cytotoxic cDC subset as well as reducing Treg abundance (Molenkamp et al. 2007; Hofmann et al. 2008). In another phase II clinical trial also, subcutaneous

9.3

Targeting pDCs in Cancer

153

CpG injection demonstrated efficacy in stimulating anti-tumor immunity in patients with MM (Pashenkov et al. 2006). Agatolimod or CpG-7909, a synthetic oligonucleotides with TLR9 agonism, has been shown to glean significant benefit in clinical outcomes when used with EGFRantagonist erlotinib in EGFR+ non-small cell lung carcinoma (Murad et al. 2007; Belani et al. 2013). A synthetic oligonucleotide TLR9 agonist (immunomodulatory oligonucleotides or IMO), IMO-2055, has been tried in several trials involving different tissue-origin cancer, viz. non-small cell lung carcinoma and colorectal carcinoma, and has been shown to have acceptable safety profile and promise for clinical efficacy (Kandimalla et al. 2005; Smith et al. 2014; Chan et al. 2015). Yet another synthetic oligonucleotides TLR9 agonist, CpG-28, was tried in glioblastoma involving intrathecal injection of the agonist. The safety profile was found acceptable but therapeutic efficacy was not optimal (Ursu et al. 2017). Another TLR9 agonist, MGN1703, was tested as a maintenance regime in a clinical trial in metastatic colorectal carcinoma following chemotherapy, wherein a good safety profile and considerable therapeutic efficacy was registered (Schmoll et al. 2014; Wittig et al. 2015). Finally, the immunoregulatory molecules in pDCs, which are responsible for the intra-tumoral reprogramming for immune tolerance, can be targeted for achieving a pro-tumor phenotype of pDCs in the tumor microenvironment and enhance antitumor immunity. Several molecules, for example, the established immune checkpoint molecules, ICOS, BDCA2 as well as oncometabolite receptors like GPR81 or MCTs can be targeted during ex vivo pDC maturation and loading with tumor antigens. However, such strategies are not yet widely explored in solid tumors. Nevertheless, targeting pDC-intrinsic molecules is a tested therapeutic strategy in hematologic malignancies, primarily in pDC-origin neoplasia. As discussed before, blastic plasmacytoid dendritic cell neoplasm (BPDCN) and acute myelogenous leukemia with clonal expansion of pDC (PDC-AML) are characterized by expansion of pDCs which express the characteristic surface molecules CD123 and BDCA2. Targeting of CD123 has been successfully used in both BPDCN and PDC-AML (DiPippo et al. 2021; Wilson et al. 2022). A cytotoxic fusion protein, Tagraxofusp, which targets CD123-expressing cells in the body, is now approved by FDA for BPDCN (Jen et al. 2020; Díaz Acedo et al. 2022). Tagraxofusp consists of IL-3 fused to diphtheria toxin. When IL-3 binds to its receptor CD123 and gets internalized, the cell dies due to inhibition of protein synthesis by the toxin. This pDC depletion therapy has been proven useful in BPCDN, but as recurrence is quite frequent in these cancers other pDC molecules are also testable candidates for second-line therapy. BDCA2 is suggested to be a potential target as preclinical data suggests considerable efficacy of targeting this molecule in different clinical contexts (Wilson et al. 2022).

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PDC-Based Vaccines for Cancer

Dendritic cell based vaccination is based on the antigen presentation function of the DCs and thus cDCs are usually employed for designing tumor antigen-specific vaccines (Baxevanis et al. 2020). The prototypical cDC-based vaccine with demonstrated anti-cancer efficacy is Sipuleucel-T approved for metastatic prostate cancer (Kantoff et al. 2010). The vaccination strategy involves collection of autologous cDCs from peripheral blood of patients, loading them with tumor antigen in vitro in the presence of DC maturating conditions and growth factor, followed by infusing them back into the patients. The vaccination leads to cDCs presenting tumor-specific antigens to T cells which are recruited to the tumor and drive the anti-cancer response (Madan et al. 2020). Given the established supremacy of cDCs in antigen presentation function and the considering data on intra-tumoral dysfunction and pro-tumor polarization of pDCs (discussed in detail in a previous chapter), the later has been less explored in DC vaccination efforts. Nevertheless, in one such effort, HLA-matched allogeneic pDCs loaded with tumor antigens were capable of activating antigen-specific response with recipient peripheral blood mononuclear cells as well as in a humanized mouse (Aspord et al. 2010, 2012). Autologous pDCs, activated and loaded with tumor-specific antigens ex vivo, when injected back into the lymph nodes of patients was also found to drive activation of T cells as well as lead to in situ type I IFN induction (Tel et al. 2013). In a more recent study Gen2.2 pDC cell line has also been used in an anti-cancer vaccine strategy against melanoma. Allogeneic Gen2.2 cells loaded with multiple tumor antigens were able to drive antigen-specific memory T cell expansion in patients with no discernible alloimmune response (Charles et al. 2020). Moreover, addition of antibody to the immune checkpoint molecule PD1 further enhanced the T cell priming ability of the pDCs in vitro.

9.4

Conclusion

Therapeutic targeting of pDCs take into account the diverse functions these cells play in different clinical contexts. It ranges from the type I IFN induction by pDCs in response to endosomal TLR activation to its proinflammatory as well as tolerogenic antigen presentation functions. Thus diverse strategies, viz. small molecules or oligonucleotides targeting endosomal TLRs, monoclonal antibodies targeting pDCs as well as type I IFN responses, cellular therapies employing pDCs themselves, are being tried depending on the specific clinical contexts and the intended therapeutic outcomes.

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Abbreviations

2-AG ABHD6 AEA BCL11A BDCA2 BPDCN CB1 CB2 CCR10 CCR2 CCR6 CDC CDP CMKLR1 CSF1R CXCR4 DC DNFB dsDNA dsRNA FAAH FLT3 FoxP3 GAS GM-CSF GVHD HSC ICOS

2-arachidonyl glycerol Alpha/beta-hydrolase domain containing 6 N-arachidonoylethanolamine B cell leukemia/lymphoma 11A Blood dendritic cell antigen 2 Blastic plasmacytoid dendritic cell neoplasia Cannabinoid receptor 1 Cannabinoid receptor 2 C-C chemokine receptor type 10 C-C chemokine receptor type 2 C-C chemokine receptor type 6 Conventional dendritic cell Common dendritic cell precursor Chemokine like receptor 1 Colony stimulating factor 1 receptor C-X-C chemokine receptor type 4 Dendritic cell Dinitrofluorobenzene Double-stranded DNA Double-stranded RNA Fatty acid-amide hydrolase Fms-like tyrosine kinase 3 Forkhead box P3 Gamma-activated sequences Granulocyte monocyte colony stimulating factor Graft versus host disease Hematopoietic stem cell Inducible T-cell costimulator

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 D. Ganguly, Plasmacytoid Dendritic Cells, https://doi.org/10.1007/978-981-19-5595-2

161

162

IDO IFNAR IFN-α IFN-β IFN-γ IKKε IL-1 IL-10 IL-12 IL-4 IL-6 IL-7R IL-8 IRF7 IRF8 ISRE iTreg JAK LRR LXR MAGL MAPK MCSF MCT MDP MTG16 mTOR Myd88 NAFLD NASH NFκB nTreg PDC PTEN RA RIG-I Siglec-H SLE SS SSc ssDNA ssRNA STAT STING

Abbreviations

Indoleamine 2, 3-dioxygenase Interferon alpha receptor Interferon α Interferon β Interferon γ IκB kinase-ε Interleukin 1 Interleukin 10 Interleukin 12 Interleukin 4 Interleukin 6 Interleukin 7 receptor Interleukin 8 Interferon regulatory factor 7 Interferon regulatory factor 8 IFN-stimulated response elements Induced T regulatory cells Janus kinase Leucine-rich-repeat Liver X receptor Monoacylglycerol lipase Mitogen-activated protein kinase Monocyte colony stimulating factor Monocarboxylate transporter Monocyte dendritic cell precursor Myeloid translocation gene on chromosome 16 Mammalian target of rapamycin Myeloid differentiation primary response protein 88 Nonalcoholic fatty liver disease Nonalcoholic steatohepatitis Nuclear factor-κB Natural T regulatory cells Plasmacytoid dendritic cell Phosphoinositide 3-kinase (PI3K)-mTOR negative regulator Rheumatoid arthritis Retinoic acid-inducible gene I Sialic-acid-binding Ig-type lectin H Systemic lupus erythematosus Sjogren syndrome Systemic sclerosis Single-stranded DNA Single-stranded RNA Signal transducer and activator of transcription Stimulator of interferon genes

Abbreviations

SYK T1DM T2DM TBK1 TCR TGF-β THC TIR TIRAP TLR TNF-α TRAM TRIF TSLP

163

Spleen tyrosine kinase Type 1 diabetes mellitus Type 2 diabetes mellitus TANK-binding kinase 1 T cell receptor Transforming growth factor-β Δ9-Tetrahydrocannabinol Toll/IL-1 receptor TIR domain-containing adaptor protein Toll-like receptor Interferon α TRIF-related adaptor molecule TIR domain-containing adaptor protein inducing IFNβ Thymic stromal lymphopoietin