Immunoregulatory Semaphorin Receptor CD72

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Immunoregulatory Semaphorin Receptor CD72 Atsushi Kumanogoh and Hitoshi Kikutani* Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan * corresponding author tel: +81-6-6879-8363, fax: +81-6-6875-4465, e-mail: [email protected] DOI: 10.1006/rwcy.2002.1421.

SUMMARY CD72, which was initially identified as mouse Lyb-2 surface protein, is a type II transmembrane glycoprotein belonging to the C-type lectin family. Although crosslinking of CD72 by monoclonal antibodies (mAbs) enhances B cell activation, CD72 has immunoreceptor tyrosine-based inhibitory motifs (ITIMs), suggesting that it functions as a negative regulator of B cell responses. CD100 binds to CD72 and enhances B cell responses by turning off negative signals of CD72.

BACKGROUND

Discovery CD72 was originally identified as Lyb-2 cell surface glycoprotein with its expression restricted to B lineage cells (Sato and Boyse, 1976; Yakura et al., 1981). Conventional antisera and monoclonal antibodies (mAb) identified three allotypes of Lyb-2 antigen, Lyb-2.1, Lyb-2.2, and Lyb-2.3. Molecular cloning revealed that Lyb-2 is a 45 kDa type II transmembrane protein that belongs to the C-type lectin family (Nakayama et al., 1989; Von Hoegen et al., 1990). CD72 is expressed throughout B cell differentiation from the earliest B cell progenitors to mature B cells,

Cytokine Reference

but the expression is downregulated upon terminal differentiation into plasma cells (Nakayama et al., 1989; Von Hoegen et al., 1990; Tutt Landolfi and Parnes, 1997).

Alternative names Lyb-2, Ly-19.2, Ly-32.2 (mouse)

Structure CD72 is a type II transmembrane glycoprotein expressed as a disulfide-linked homodimer. Another structural feature is a C-type lectin domain in the extracellular region.

Main activities and pathophysiological roles A number of studies of the stimulating effects of antiCD72 mAbs have been reported (Gordon, 1994; Gordon et al., 1991; Kamal et al., 1991; Katira et al., 1992; Nomura et al., 1996; Yakura et al., 1982, 1986). Crosslinking of CD72 can transform a subset of small resting B cells into blast cells and induce proliferation of activated B cells. Anti-CD72 mAbs block B cell

Copyright # 2002 Published by Elsevier Science Ltd

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Atsushi Kumanogoh and Hitoshi Kikutani

receptor (BCR)-mediated cell death, promote B cell survival and proliferation, increase MHC class II expression and enhance production and shedding of CD23 in B cells. Many of the effects of anti-CD72 mAbs on resting B cells are relatively weak, but are enhanced significantly by CD40 stimulation. In some situations, IL-4 and CD72 signals act in synergy with one another. These effects of anti-CD72 mAb are similar to those of recombinant soluble CD100 and CD100-expressing transfectants. For instance, CD100 synergistically enhances CD40-induced B-cell responses. In addition, stimulation with human CD100 enhances the shedding of CD23 from the surface of B cells (Hall et al., 1996; Kumanogoh et al., 2000).

GENE

Accession numbers Human: NM_001782 Mouse: NM_007654

Chromosome location Human 9q

Figure 1

Amino acid sequence for CD72.

Human CD72 MAEAITYADL DKAAVKSEQP VSQQLQQTNR AEGQLQACQA QKSCFYISLT LSSNKDWKLT

RFVKAPLKKS TASWRAVTSP VLEVTNSSLR DRQKTKETLQ SKNWQESQKQ DDTQRTRTYA

ISSRLGQDPG AVGRILPCRT QQLRLKITQL SEEQQRRALE CETLSSKLAT QSSKCNKVHK

ADDDGEITYE TCLRYLLLGL GQSAEDLQGS QKLSNMENRL FSEIYPQSHS TWSWWTLESE

NVQVPAVLGV LLTCLLLGVT RRELAQSQEA KPFFTCGSAD YYFLNSLLPN SCRSSLPYIC

PSSLASSVLG AICLGVRYLQ LQVEQRAHQA TCCPSGWIMH GGSGNSYWTG EMTAFRFPD

ASNHLGQDCE LRQIPRCPTV QLREKISQLG EERRRDLDQR LSSKLAAFDE DKIKKYYQKW

AYEDGELTYE CLQNFLLGLL QKEVEQESQK LTSTRETLRR PSKYYYEYLS KRTFSECAEL

NVQVSPVPGG LSCLMLGVAV ELISSQDTLQ LSSCSSDTCC DAPQVSLPSG HPCICESEAF

PGLASPALAD ICLGVRYLQV EKQRTHKDTE PCGWIPYQER LEELLDRSKS RFPDGIHLN

Mouse CD72 MADAITYADL KAGVGSEQPT SQQFQEGTRI QQLQACQAER CFYISHTLRS YWIQMSKKWR

RFVKVPLKNS ATWSSVKSSA WEATNSSLQQ AKTKENLKTE LEESQKYCTS HDYDSQSRYC

potential N-linked glycosylation site in the C-terminal end of the protein. The cytoplasmic domain of CD72 contains an immunoreceptor tyrosine-based inhibitory motif (ITIM), to which SHP-1, a tyrosine phosphatase, is recruited (Adachi et al., 1998, 2001). SHP-1 has been shown to associate with many inhibitory receptors, such as CD22 and killer inhibitory receptors, through their ITIM motifs and to inhibit the functions of immune cells, including B cells and NK cells, by inducing tyrosine dephosphorylation and inactivation of signaling proteins (Tedder et al., 1997; Lanier, 1998; Falco et al., 1999). Thus, CD72 is thought to function as a negative regulator.

PROTEIN

Accession numbers Human: NP_001773 Mouse: P21855

Sequence See Figure 1.

Description of protein CD72 is a type II transmembrane glycoprotein expressed on the cell surface as an 86 kDa disulfidelinked homodimer (Von Hoegen et al., 1990). Immunoprecipitation under reducing conditions generates a 42 kDa major band and a 40 kDa minor band, probably due to the differences in glycosylation in the extracellullar region. Endoglycosidase F treatment results in a 2±3 kDa reduction in apparent molecular weight, which is consistent with the presence of one

Relevant homologies and species differences The cDNA for three alleles of mouse CD72 have been cloned and these allelic polymorphisms are seen in the membrane-distal portion of the extracellular domain (Robinson et al., 1992; Ying et al., 1995). The degree of polymorphism in human CD72 has as yet not been reported.

Affinity for ligand(s) The binding affinity (Kd) between CD100 and CD72 is approximately 3  10 7 M (Kumanogoh et al., 2000).

Cell types and tissue expressing the receptor CD72 is expressed throughout B cell differentiation from early B cell progenitors to mature B cells but the

Immunoregulatory Semaphorin Receptor CD72 3 expression is downregulated upon terminal differentiation into plasma cells. In addition to B cells, DCs, macrophages, and some subpopulations of T cells are known to express this molecule (Robinson et al., 1997; Tutt Landolfi and Parnes, 1997; Kumanogoh et al., 2002). The expression of CD72 is also found on macrophages in the splenic red pulp and liver Kupffer cells (Tutt Landolfi and Parnes, 1997).

SIGNAL TRANSDUCTION

Associated or intrinsic kinases Several biochemical studies using anti-CD72 mAbs suggest that CD72 may transduce positive signals for B cell responses. Inositol 1,4,5-trisphosphate (IP3) and Ca2+ appear to be important in the signal transduction pathway of CD72. Mouse antiCD72 weakly induces phosphatidylinositol turnover (Grupp et al., 1987) and induces an early increase in Ca2+ responses (Subbarao et al., 1988). Protein tyrosine phosphorylation also appears to be involved in the CD72 signaling pathway. Anti-CD72 induces tyrosine phosphorylation of a variety of proteins in mouse splenic B cells, including phospholipase C- 2 and CD19, and activates Lyn, Blk, and Btk kinases (Venkataraman et al., 1998a,b). In addition, crosslinking of CD72 induces transient association of CD72 with CD19, which is known to be a positive regulator of BCR responses (Tedder et al., 1997). However, there are several pieces of evidence that suggest a potential role for CD72 as a negative regulator of B cell responses. Like other inhibitory receptors, CD72 contains two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in its cytoplasmic domain and recruits SHP-1 (Adachi et al., 1998). Moreover, B cells of CD72-deficient mice are hyperresponsive to various stimuli (Pan et al., 1999). Interestingly, either agonistic antiCD72 or soluble CD100 can block tyrosine phosphorylation of CD72 and the association of SHP-1 with CD72, both of which are induced by anti- stimulation (Wu et al., 1998; Kumanogoh et al., 2000) These findings suggest that CD100 enhances B cell responses by turning off the negative-signaling effects of CD72, and agonistic anti-CD72 mAbs probably mimic the effects of CD100. Consequently, negative signaling through CD72 appears to be aberrantly active in B cells from CD100-deficient mice, in which CD72 is constitutively tyrosinephosphorylated and associated with SHP-1 (Shi et al., 2000).

BIOLOGICAL CONSEQUENCES OF ACTIVATING OR INHIBITING RECEPTOR AND PATHOPHYSIOLOGY

Unique biological effects of activating the receptors Cumulative evidence from in vitro studies using antiCD72 mAb suggests that CD72 is an important costimulatory molecule for B cell activation (Gordon, 1994). Engagement of CD72 by its mAb can transform a subset of small resting B cells into blast cells and induce proliferation of both resting and activated B cells. Engagement of mouse CD72 enhances the B cell proliferative response to either IL-4 or anti-IgM and synergizes with IL-1 in the induction of B cell proliferation. Furthermore, mouse anti-CD72 mAb causes a modest increase of class II major histocompatibility complex (MHC) gene expression on splenic B cells. These effects of antiCD72 mAbs are similar to those of soluble CD100 and CD100 transfectants. Although CD100 stimulation alone exerts little effect, recombinant soluble CD100 or CD100-expressing transfectants synergistically enhance CD40-induced B cell responses (Kumanogoh et al., 2000). In addition, stimulation by human CD100 has been demonstrated to enhance the shedding of CD23 from the cell surface of B cells (Hall et al., 1996). Furthermore, both anti-CD72 and soluble CD100 enhance CD40-induced IL-12 production by DCs (Kumanogoh et al., 2002).

Phenotypes of receptors knockouts and receptor overexpression mice B cells from CD72-deficient mice hyperproliferate in response to various stimuli and have a more rapid Ca2+ response following BCR stimulation, indicating that CD72 functions as a negative regulator for B cell responses (Pan et al., 1999). The phenotypes of CD100-deficient mice seem to be the opposite of those of CD72-deficient mice (Pan et al., 1999; Shi et al., 2000), which also suggests that CD100 may switch off negative signals of CD72. CD72-overexpressing transgenic mice have not as yet been reported.

Human abnormalities CD72 is expressed on many non-Hodgkin's B cell lymphomas examined, including pre-B cell, Burkitt's,

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and germinal center-derived lymphomas (Schwarting et al., 1992). In addition, acute B cell leukemia representing the full range of B cell differentiation expressed CD72. CD72 is also present on many acute lymphoblastic leukemias (Myers and Uckun, 1995).

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Immunoregulatory Semaphorin Receptor CD72 5 Yakura, H., Shen, F. W., Bourcet, E., and Boyse, E. A. (1982). Evidence that Lyb-2 is critical to specific activation of B cells before they become responsive to T cell and other signals. J. Exp. Med. 155, 1309±1316. Yakura, H., Kawabata, I., Ashida, T., Shen, F. W., and Katagiri, M. (1986). A role for Lyb-2 in B cell activation

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