Role of Inhibitory BCR Co-Receptors in Immunity

Infectious Disorders – Drug Targets, 2012, 12, 181-190 181 Role of Inhibitory BCR Co-Receptors in Immunity

Takeshi Tsubata*

Laboratory of Immunology, Tokyo Medical and Dental University Graduate School of Biomedical Sciences, 1-5-45 Yu- shima, Bunkyo-ku, 113-8510 Tokyo, Japan

Abstract: B lymphocytes (B cells) express a variety of membrane molecules containing immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the cytoplasmic region such as FcRIIB, FCRLs, CD22, mouse Siglec-G/human Siglec-10, PECAM-1, mouse PIR-B/human LIRB1 and LIRB2PD-1 and CD72. When phosphorylated, ITIMs in these molecules recruit and activate phosphatases such as SH2 domain-containing protein tyrosine phosphatase 1 (SHP-1), SHP-2, SH2 domain-containing inositol 5-phosphatase 1 (SHIP1) and SHIP2 depending on receptors. These phosphatases then negatively regulate B cell antigen receptor (BCR) signaling. Because of their ability to inhibit BCR signaling, these ITIM- containing molecules are called inhibitory BCR co-receptors. Studies on mice deficient in an inhibitory co-receptor have demonstrated that the inhibitory co-receptors regulate B cell development, antibody responses and development of autoimmune diseases. Moreover, polymorphisms in some inhibitory co-receptors such as FcRIIB, FCRL3 and CD72 are associated with autoimmune diseases, suggesting a crucial role of inhibitory co-receptor polymorphisms in the regulation of autoimmune diseases. The ligands for inhibitory co-receptors regulate their inhibitory activity by inducing co-ligation of the co-receptors with BCR or some other regulatory mechanisms. Inhibitory co-receptors and their ligands are therefore good targets for controlling antibody responses and autoimmune diseases. Keywords: B cell, antibody response, autoimmune disease, FcR, CD22, Siglec.

INTRODUCTION phosphorylated probably because they get close to the BCR- activated kinase such as Lyn, leading to strong down- It is already established that B cell antigen receptor modulation of BCR signaling [3, 4]. When BCR is ligated by (BCR) signaling is regulated by various membrane mole- the immune complex composed of the antigen and IgG, the cules either positively or negatively. Membrane molecules antigen and IgG in the immune complex bind to BCR and such as CD22, CD72, PIR-B, FcRIIB, PD-1, PECAM-1 and FcRIIB, respectively, resulting in co-ligation of BCR and FCRLs negatively regulate BCR signaling (Table 1), and are FcRIIB. FcRIIB then efficiently regulates BCR signaling thus called as inhibitory BCR co-receptors, whereas BCR (Fig. 1A). This negative regulation of B cell activation in- signaling is up-regulated by membrane molecules such as duced by immune complex appears to be involved in nega- CD19. Inhibitory BCR co-receptors contain one or more tive feedback regulation of IgG production. In contrast, immunoreceptor tyrosine-based inhibition motif (ITIMs) in CD22 recognizes 2,6-linked sialic acid as a ligand [5]. the cytoplamic region characterized by the consensus se- Sialic acids are a family of acidic sugars typically found at quence (Ile/Val/Leu/Ser)-x-Tyr-x-x-(Leu/Val) [1]. ITIMs are the outer termini of glycoproteins and glycolipids in animals, phosphorylated by Src family kinases at the tyrosine residue whereas microbes do not produce sialic acids with rare ex- [2]. Some of the inhibitory BCR co-receptors such as CD22 ceptions. Thus, sialic acids are a good target of immune sys- and FcRIIB are demonstrated to be phosphorylated by the tem to distinguish host cells from microbes. When BCR in- Src family kinase Lyn that is activated upon BCR ligation [3, teracts with antigens containing 2,6 sialic acid, CD22 is 4]. When phosphorylated at the tyrosine residue, the ITIMs efficiently phosphorylated and down-modulates BCR signal- recruit phosphatases such as SH2 domain-containing protein ing probably because CD22 is co-ligated with BCR (Fig. 1D) tyrosine phosphatase (SHP)-1, SHP-2, SH2 domain- [6]. Down-modulation of BCR signaling by sialylated anti- containing inositol 5-phosphatase 1 (SHIP1) and SHIP2 de- gens may be involved in self-tolerance by inhibiting anti- pending on co-receptors [2]. The phosphatases recruited to body production to sialylated self-antigens. the inhibitory BCR co-receptors down-modulate BCR signaling by dephosphorylating signaling molecules activated As inhibitory BCR co-receptors negatively regulate B through phosphorylation upon BCR ligation. cell activation upon BCR ligation, it is not surprising that some of these co-receptors play a role in inhibiting develop- Ligand binding activities are defined in the extracellular ment of autoimmune diseases. Mice deficient in FcRIIB [7], region of some inhibitory BCR co-receptors such as CD22 CD72 [8], PECAM-1 [9] or PD-1 [10] spontaneously de- and Fc RIIB, and appear to play a crucial role in the regula- velop lupus-like autoimmune diseases. In humans, genetic tion of B cell activation. Ligand binding determines whether studies demonstrated that polymorphisms in some genes the inhibitory BCR co-receptors are co-ligated with BCR. encoding inhibitory BCR co-receptors such as FcRIIB [11- When co-ligated with BCR, these co-receptors are efficiently 14] and FCRL3 [15-17] are associated with various autoimmune diseases including systemic lupus erythematosus *Address correspondence to this author at the Laboratory of Immunology, (SLE) and rheumatoid arthritis (RA). In this review, I dis- Tokyo Medical and Dental University Graduate School of Biomedical Sci- cuss the role of CD22 and other inhibitory BCR co-receptors ences, 1-5-45 Yushima, Bunkyo-ku, 113-8510 Tokyo, Japan; Tel: +81-3- in the regulation of B cell activation and immune responses 5803-5817; Fax: +81-3-5684-0717; E-mail: [email protected] including autoimmunity.

Table 1. Inhibitory BCR Co-Receptors

Spontaneous Auto- Association with Extracellular Association Expression Ligands immune Diseases in Autoimmune Dis- Region Molecules Knock out Mouse eases in Human

FcRIIB B,DC,M,Gr Ig domains IgG SHIP Lupus-like SLE

Human FCRL2 B Ig domains ? SHP1

SHP1, SHP2, Syk, Human FCRL3 B, T, NK Ig domains ? SLE, RA, thyroiditis Zap70

Human FCRL4 B Ig domains ? SHP1, SHP1, PLC

Human FCRL5 B Ig domains ? SHP1

Mouse FCRL5 B Ig domains ? ?

SHP1, Syk, PLC, Lupus-like (CD22 CD22 B Ig domains 2,6 Sialic acid PI3K, Grb2 SiglecG double ko)

Sialic acid Lupus-like (CD22 Mouse Siglec-G B Ig domains ? (2,6>2,3) SiglecG double ko)

Human Sialic acid B, (Gr) Ig domains SHP1 Siglec-10 (2,6>2,3)

B, T, Mo, Gr, NK, PECAM-1 Ig domains PECAM-1 SHP2 Lupus-like P, endothel

B, Mast, M, N, Mouse PIR-B Ig domains MHC I SHP2>SHP1 DC, osteoclast

Human LILRB1 B, Mo, (DC) Ig domains MHC I SHP1, CSK

Human LILRB2 B, Mo, (DC) Ig domains MHC-I ?

B, T, DC PD-1 Ig domains PDL1, PDL2 SHP2 Lupus-like, carditis (Activated)

C-type lictin-like CD72 B CD100 SHP1, SHP2, Grb2 Lupus-like SLE, ITP domain

Gr: Granulocytes, Mo:monocytes, M, Macrophage; P, Platelet.

SHP-1 plays a dominant role over Syk and PLC, thereby CD22 AND ITS GLYCAN LIGAND negatively regulating BCR signaling. CD22 (also known as Siglec-2) is a member of the Siglec The extracellular region of CD22 contains 7 Ig-like do- (sialic-acid-binding immunoglobulin-like lectins) family and mains, and the N terminal domain binds to 2,6-linked sialic expressed mostly on B cells. Among 6 tyrosines in the cyto- acids [5, 29, 30]. As already discussed, CD22 recognition of plamic region of CD22, 3 tyrosines and their flanking se- sialic acids may be involved in inhibition of immune re- quences were initially demonstrated to match the consensus sponses to self-antigens. Sialic acids are modified at C-4, C- sequence of ITIM and to be binding sites for SHP-1 [18-20]. 5, C-7, C-8 and C-9 positions, resulting in various molecular We later showed that the cytoplamic region of CD22 con- species. Modification at C-5 generates N-acetylneuraminic tains 4 ITIMs that recruit SHP-1 [21]. These ITIMs include 2 acid (Neu5Ac), N-glycorylneuraminic acid (Neu5Gc), 2- most C terminal tyrosines, whose flanking sequences also keto-3 deoxy-D-glycero-D-galactononic acid (KDN) and show homology to immunoreceptor tyrosine-based activa- neuraminic acid (Neu). These four molecules are further tion motif (ITAM). CD22 associates with signaling mole- modified by various modifications such as acetylation at the cules such as the tyrosine kinase Syk and phospholipase C other positions. Among various silalic acid species, ligand- (PLC) most likely at this ITAM [22, 23]. Thus, CD22 ap- binding specificity of mouse CD22 differs from that of hu- pears to contain both ITIMs and ITAM, and this finding man CD22. Mouse CD22 prefers Neu5Gc over Neu5Ac, suggests that it carries both inhibitory and stimulatory activ- whereas human CD22 recognizes both Neu5Gc and Neu5Ac ity. However, studies with CD22-deficient B cells and B cell [31, 32]. Interestingly, synthesis of these sialic acid species lines clearly demonstrated that CD22 negatively regulates is different between human and mouse. Human produces BCR signaling [24-28]. Thus, CD22 is able to recruit signal- Neu5Ac but not Neu5Gc because the gene for CMP-Neu5Ac ing molecules such as Syk and PLC as well as SHP-1, but Inhibitory BCR Co-Receptors Infectious Disorders – Drug Targets, 2012, Vol. 12, No. 3 183

Fig. (1). Detection of negative regulation of BCR signaling by inhibitory BCR co-receptors. (A) BCR ligation by immune complex consisting of IgG and antigen co-ligate FcRIIB with BCR. Co-ligation brings FcRIIB to the proxility of BCR, and causes efficient phosphorylation of FcRIIB at cytoplasmic ITIMs by the tyrosine kinase Lyn that is activated by BCR ligation. Phosphorylated ITIMs then recruit and activate the lipid phosphatase SHIPs, which down modulate BCR signaling. In contrast, BCR ligation by antigen alone does not induce FcRIIB- mediated signal regulation. (B) Intact anti-IgM antibody (IgG) co-ligates FcRIIB with BCR, where as FcRIIB is not co-ligated by F(ab’)2 fragments of anti-IgM antibody that lack the Fc portion. Co-ligation leads to phosphorylaito of FcRIIB at ITIMs and down-modulation of BCR signaling. (C) To address whether ITIM-containing receptors are able to down-modulate BCR signaling, a fusion protein containing the extracellular part of FcRIIB and the cytoplamic region of ITIM-containing receptors is expressed on B cells, and is co-ligated with BCR using intact anti-IgM antibody. The ability of ITIM-containing receptors to regulate BCR signaling is proved when co-ligation induces phosphorylation of ITIMs and down modulation of BCR signaling. (D) Some inhibitory BCR co-receptors such as CD22 are phosphorylated when BCR is ligated even in the absence of apparent co-ligation with the inhibitory co-receptors. Down modulation of BCR signaling by these co- receptors can be detected by comparison between B cells that express a BCR co-receptor and those that do not. When BCR is ligated by the antigen that contains the ligand for the inhibitory co-receptor (sialic acids for CD22), the inhibitory co-receptor is co-ligated BCR leading to stronger ITIM phosphorylation and signal regulation. 184 Infectious Disorders – Drug Targets, 2012, Vo l. 12, No. 3 Takeshi Tsubata hydroxylase (CMAH), the enzyme required for Neu5Gc syn- studies are required to understand the role of the glycan thesis, is deficient due to null point mutation, whereas mice ligand for CD22. produce both Nue5Ac and Neu5Gc [33, 34]. Thus, both hu- In mice, B cells in germinal centers do not express man and mouse CD22 have endogenous glycan ligand, al- Neu5Gc because of specific down-regulation of CMAH ex- though both ligand-binding specificity of CD22 and produc- pression [43]. As a consequence, CD22 on germinal center B tion of sialic acid species are different between human and cells are not able to interact with its cis ligand. Recent study mice. by Kimura et al., demonstrated that 2,6-sialylated 6-sulfo- As already discussed, CD22 efficiently down-modulates N-acetyllactosamine is the preferred ligand for human CD22, BCR signaling when B cells interact with sialylated antigens. and expression of this preferred ligand is lost in germinal Nonetheless, CD22 down-modulates BCR signaling to some centers [44]. Thus, germinal center B cells lose preferred cis extent when BCR is ligated by unsialylated proteins such as ligand for CD22 in both human and mice through distinct bovine serum albumin (BSA) [35]. Thus, CD22 contributes mechanisms. Signal regulation activity of CD22 may be al- to distinction between self and microbes by efficiently down- tered in germinal center B cells by loss of cis ligand expres- modulates BCR signaling to sialylated antigens, but also sion although the biological significance of this phenomenon plays a role in setting a threshold for B cell activation [36] is not yet understood. by generally down-modulating BCR signaling even when interacted with non-sialylated antigens Fig. (1D). CD22 REGULATES ANTIBODY PRODUCTION To address the role of CD22 in immunity, CD22- ROLE OF ENDOGENOUS CIS GLYCAN LIGAND deficient mice were generated in 4 groups [24-27]. Antibody FOR CD22 production to T cell-dependent antigens in CD22-deficient B lymphocytes express a large amount of 2,6-linked mice was not augmented except for the finding of one group, sialic acids probably due to high expression of 2,6 sialyl and that to T cell-independent antigens was rather reduced. transferase I (ST6GalI) required for synthesis of 2,6-linked Normal or reduced antibody production in the presence of sialic acids. As a result, most of the CD22 molecules ex- augmented B cell signaling suggests that loss of CD22 may pressed on a B cell are bound by the glycan ligand expressed also play an inhibitory role in antibody production. CD22- on the same cell (cis interaction) [37]. The finding that sialy- deficient B cells rapidly undergo apoptosis when cultured in lated antigen induces strong CD22-mediated signal inhibi- vitro and show reduced longevity in vivo [25]. Rapid apopto- tion [6] suggests that trans ligands are able to interact with sis might limit antibody production in CD22-deficient mice. CD22 even in the presence of CD22 masking by cis ligands. Alternatively, CD22-deficiency expands the number of B cells capable of producing IL-10 [45]. These cells are called Evidence suggests that the cis ligand regulates inhibitory as regulatory B cells (B reg cells) because IL-10 inhibits T activity of CD22. Mice deficient in ST6GalI fail to synthe- size 2,6-linked sialic acids, and show both reduced BCR cell responses by suppressing antigen-presenting cells. In CD22-deficient mice, expanded B reg cells may down- signaling and reduced antibody production [38], demonstrat- modulate T cell-dependent antibody production. Whether ing that 2,6-linked sialic acids augment BCR signaling. these suppressive effects of CD22 deficiency involves aug- Reduction of BCR signaling by loss of ST6GalI requires mented BCR signaling is not yet known. CD22 because the ST6GalI/CD22 double-deficient mice show augmented BCR signaling as is the case for CD22 sin- As the earlier studies did not address the B lymphocyte gle deficient mice [39]. ST6GalI deficiently probably en- activation at the early phase of immune responses, we ad- hances CD22-mediated signal inhibition. Conversely, the dressed the proliferation of CD22-deficient B cells and their endogenous glycan ligand suppresses CD22-mediated BCR differentiation to plasma cells within one week after immu- signal inhibition. Thus, 2,6-linked sialic acids appear to be nization [46]. When we immunized the recipient mice trans- a negative regulator of the inhibitory activity of CD22. ferred with nitrophenol (NP)-reactive CD22-deficient B In contrast, there is also evidence suggesting that the en- cells, these B cells rapidly expanded and differentiated to plasmablasts in 3 days like memory B cells. However, the dogenous glycan ligand augments CD22-mediated signal number of plasma cells was decreased after day 5 to the level inhibition. O-acetylation at the C-9 position is a common equivalent to that of CD22-sufficient B cells at day 7. Thus, modification of silaic acids, and this modification on 2,6- CD22-deficient B cells undergo rapid antibody responses linked sialic acids impairs its binding to CD22 [40]. Mice like memory B cells at the early phase of immune response, deficient in sialic acid acetyl esterase (SIAE), an enzyme that removes acetyl group from the C-9 position of sialic acids but their response is prematurely regressed probably by enhanced cell death. Because of the premature regression of the [41], show reduced SHP-1 recruitment to CD22, and aug- B cell response, earlier studies failed to detect early expan- mented BCR signaling [42]. As SIAE-deficiency causes in- sion and differentiation of CD22-deficient B cells. creased 9-O-acetylation that disrupts binding of 2,6-linked sialic acids to CD22, this finding suggests that disruption of Early antibody production is characteristic of memory ligand binding reduces CD22-mediated signal inhibition. response, and plays a crucial role in host defense against Thus, the glycan ligand appears to positively regulate the pathogens. Rapid antibody production can eliminate patho- inhibitory activity of CD22. As there is opposing evidence as gens before symptoms are developed, thereby protecting host to whether the endogenous glycan ligand regulates the sig- from infectious diseases. Membrane-bound IgG (mIgG) ex- naling function of CD22 positively or negatively, further pressed on the majority of memory B cells appear to be involved in rapid B cell response during memory responses as Inhibitory BCR Co-Receptors Infectious Disorders – Drug Targets, 2012, Vol. 12, No. 3 185 the IgG-transgenic mice where mIgG is expressed as BCR volvement of FcRIIB in the regulation of autoimmunity was on naïve B cells show rapid antibody responses as is the case clearly demonstrated by the study on FcRIIB-deficient of memory responses [47, 48]. Either quantitative or qualita- mice. These mice on C57BL/6 but not BALB/c background tive difference between signaling through mIgG and that spontaneously develop a lupus-like autoimmune disease [7]. through membrane-bound IgM or IgD determines whether B B cell tolerance in C57BL/6 strain of mice is less stringent cells generate rapid antibody responses. Both mIgG and than that in BALB/c [64]. Self-reactive IgG+ B cells gener- mIgM transmit signaling via Ig/Ig molecules, but mIgG is ated by the less stringent tolerance in C57BL/6 background suggested to transmit augmented signaling [35, 49, 50]. may expand in the absence of FcRIIB-mediated negative Augmented BCR signaling to both sialylated and non- regulation, leading to IgG autoantibody production that is sialylated antigens in CD22-deficient B cells may cause crucial for development of lupus [65]. In human, the rapid antibody responses as is the case for mIgG+ B cells, FcRIIB polymorphism is associated with SLE in both resulting in host protection against infectious diseases. Thus, Asians and Caucasians. Homozygosity of FcRIIB Ile232Thr CD22 is a good target to develop a new strategy for host is a risk factor for development of SLE [12, 14, 66]. The Ile- defense against infectious diseases. to-Thr substitution at position 232, located in the transmembrane region, reduces the efficiency of lipid rafts transloation FcRIIB AND Fc RECEPTOR-LIKE (FCRL) of FcRIIB [67, 68]. As lipid rafts is rich in Lyn, reduced lipid rafts localization appears to reduce its inhibitory activ- Although most of the receptors for the Fc region of IgG ity, and may enhances development of SLE. (FcRs) such as FcRI, FcRIIA, FcRIIC, FcRIIIA and FcRIIIB in humans and FcRI, FcRIII and FcRIV in mice Fc receptor-like (FCRL) molecules are a family of mole- are activating receptors, FcRIIB contains ITIM in the cyto- cules homologous to FcRs [69, 70]. The genes encoding plamic region [1, 51, 52]. FcRIIB is expressed in B cells these molecules are clustered at the chromosome region and myeloid cells such as macrophages and dendritic cells close to FcRs in both human and mice. Among 8 human (DCs). When B cells interact with the immune complex members of FCRL so far identified, FCRL 1-5 are preferen- composed of antigen and IgG, FcRIIB is co-ligated with tially expressed in B cells except for FCRL3 that are ex- BCR. This leads to its phosphorylation at ITIM followed by pressed in NK cells and T cells as well as B cells. Interest- recruitment of SHIP1 and SHIP2 but not SHP-1 or SHP-2 ingly, expression of these FCRLs varies among distinct B [51-53]. FcRIIB is the only one inhibitory BCR co-receptor cell subpopulations [71-75]. For example, FCRL1 is strongly that recruit SHIPs but not SHP-1 or SHP-2. SHIPs are the expressed in follicular mantle zones [75] where naïve B cells lipid phosphatases that hydrolyse 5-phosphate groups of reside, whereas FCRL4 is expressed in a subset of memory phophatidylinositol 3,4,5-triphosphates (PI(3,4,5)P3), thereby B cells [72, 74]. These FCRL molecules contain ITIM and generating phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) ITAM-related sequences in the cytoplasmic region. FCRL2 [54, 55]. PI(3,4,5)P3 is located in the plasma membrane, and and FCRL5 contain two ITIMs and one ITAM-like se- plays a role in activation of signaling molecules such as Btk, quence, whereas FCRL3 contains one ITIM and one ITAM- and PLC as these molecules contain pleckstrin homology like sequence [69]. When the chimeric molecule containing (PH) domains that bind to PI(3,4,5)P3 [56, 57]. Thus, SHIPs the extracellular region of Fc RIIb and the cytoplasmic re- down modulate BCR signaling by inhibiting membrane region of FCRL2, FCRL3, FCRL4 or FCRL5 is expressed and cruitment of PH domain-containing signaling molecules. co-ligated with BCR on B cell lines using anti-IgM antibody, Also, SHIPs recruit an adaptor molecule Dok-1 that associ- BCR signaling is down-modulated Fig. (1C) [76-79]. The ates with rasGAP, a negative regulator of Ras activation, cytoplamic regions of these FCRLs associate with SHP-1 leading to down modulation of ERK [58, 59]. Thus, multiple upon phosphorylation, suggesting that FCRLs negatively pathways are involved in SHIP-mediated BCR down modu- regulate BCR signaling when co-ligated with BCR by re- lation induced by FcRIIB. cruiting SHP-1. Nonetheless, the phosphorylated ITAM-like sequence of the cytoplasmic region of FCRL3 associates FcRIIB is also expressed on plasma cells, and ligation of with Syk and SHP-2 [79], and ITIMs of FCRL4 associates Fc RIIB alone on plasma cells and mature B cells induces with PLC probably by serving as an atypical ITAM [76]. apoptosis [60, 61]. Analysis on mature B cells demonstrated Thus, ITIMs play a dominant role as is the case for CD22 that this apoptosis does not require ITIM and SHIP, but ap- although FCRLs contain both ITIMs and ITAM-like se- pears to involve JNK and activation of pro-apoptotic mem- quence. Although the ligands for FCRLs are not yet identi- bers of the BCL2 family such as BID and BAD. As plasma fied, the ligands may play a role in FCRL-mediated B cell cells do not express BCR, interaction with immune com- regulation. plexes may ligate FcRIIB alone leading to apoptosis of plasma cells. Thus, FcRIIB negatively regulate plasma cell The polymorphism of FCRL3 has been shown to associ- survival by a distinct mechanism from BCR signal regula- ate with various autoimmune diseases. The initial study of tion. Japanese subjects demonstrated that a SNP located in non- coding region of the FCRL3 gene (-169T>C) associates with Several lines of evidence suggest that Fc RIIB regulates rheumatoid arthritis (RA) and other autoimmune diseases antibody production and autoimmune diseases such as SLE. such as SLE and Graves disease [15, 80]. Association of FcRIIB-deficient mice show augmented IgG production FCRL3 polymorphism with RA was also found in Chinese after immunization [62], and overexpression of Fc RIIB in B population [17], but to only a limited degree in Caucasians cells in Fc RIIB-transgenic mice causes reduction of IgG [81-85], suggesting this association is specific for Asians production [63], clearly demonstrating the negative regula- [86]. In contrast, association of this polymorphism to tory role of Fc RIIB in humoral immune responses. In- Graves’ disease was also found in Caucasians [87-89]. The - 186 Infectious Disorders – Drug Targets, 2012, Vo l. 12, No. 3 Takeshi Tsubata

169T>C polymorphism improves NF-kB binding, and con- the inhibitory activity of the co-receptors differently depend- fers increased expression of FCRL3. The finding that ing on co-receptors. development of autoimmune diseases is associated with Studies with mice deficient in these inhibitory receptors enhanced co-receptor mediated B cell inhibition is opposite such as Siglec-G [98], PECAM-1 [9], CD72 [96, 97] and to the finding on Fc RIIB. Kochi et al., proposed that PIR-B [108] demonstrated that B cells deficient in these in- reduced B cell signaling due to enhanced FCRL3 expression hibitory receptors are hyperresponsive to BCR ligation. In- may reduce the threshold of B cell tolerance thereby allow- terestingly, B cells from these knock-out mice as well as ing maturation of self-reactive B cells [15]. CD22-deficient mice also show hyper-responsiveness to TLR ligation [9, 97, 98, 109-111]. As TLR signaling does OTHER INHIBITORY BCR CO-RECEPTORS not involve tyrosine kinases, how these receptors regulate B cells express other ITIM-containing inhibitory recep- TLR signaling is not yet fully understood. Interesting clue tors such as CD72, PECAM-1, mouse PIR-B and its human was presented by Takai’s group who demonstrated that PIR- homolog LILRB1 and LILRB2, mouse Siglec-G and its hu- B regulates TLR9 signaling via Btk [111]. man homolog Siglec-10, and PD-1. CD72 is a type 2 mem- Mice deficient in the inhibitory receptors including CD72 brane protein containing a C-type lectin-like domain in the [8], PECAM-1 [9], PD-1 [10] and FcRIIB [7] develop auto- extracellular region, whereas the others are type I membrane immune diseases such as lupus-like disease. Although mice proteins containing Ig-like domains in the extracellular re- deficient in either CD22 or Siglec-G do not develop auto- gion. CD72 [90, 91] and Siglec-G [92] are predominantly immune disease, the double deficient mice produce anti- expressed in B cells, whereas the others are more widely DNA antibody and lupus-like glomerulonephritis with mas- expressed including T cells. PD-1 expression is low in rest- sive B1 cell expansion [109]. Thus, Siglec-G and CD22 may ing lymphocytes but is augmented upon activation [93]. All redundantly inhibit development of the autoimmune disease. these molecules contain ITIM and/or ITIM-like sequences As already discussed, 9-O acetylation of sialic acids disrupt that recruit SHP-1 and/or SHP-2 upon tyrosine phosphoryla- their interaction to Siglecs, and negatively regulate signal tion, and negatively regulate BCR signaling in a manner de- inhibition at least for CD22, suggesting that 9-O acetylation pendent on ITIMs [94-97]. The ability of CD72 to negatively may down-modulate signal inhibition mediated by multiple regulate BCR signaling was demonstrated by comparison Siglecs including CD22 and Siglec-G. Recently, various between CD72-deficient and CD72-sufficient B cells [95- mutations that disrupt SIAE, a negative regulator of 9-O- 97]. BCR signaling is augmented in CD72-deficient B cells acetylation of sialic acids, are found in patients with auto- compared to that in CD72-sufficient B cells. Similar findings immune diseases including SLE, type 1 diabetes and RA were obtained with Siglec-G [98] and PECAM-1 [9]. The [112]. Thus, mutations of SIAE may reverse signal regula- inhibitory activity of PD-1 [99] and PIR-B [100] was shown tion by CD22 and possibly other Siglecs including Siglec-G, using chimeric molecules containing the extracellular region thereby enhancing lymphocyte activation, and contributing of FcgIIB and the cytoplasmic region of PIR-B or PD-1 Fig. development of autoimmune diseases in humans. Moreover, (1C). Co-ligation of the chimeric molecule with BCR medi- polymorphism of CD72 is associated with human SLE in ated by anti-Ig antibody reduces BCR signaling compared to individuals carrying FCRIIB-Ile232Thr, and the presence of that induced by the F(ab)2 fragments of anti-Ig antibody that the CD72*2/2 haplotyoe eliminates the risk for SLE con- ligates BCR without binding to the Fc RIIB chimeric mole- ferred by FcRIIB-Ile232Thr [113]. Thus, inhibitory co- cule. Thus, PD-1 and PIR-B negatively regulates BCR sig- receptors regulate autoimmune diseases both in mouse and naling when these molecules are co-ligated with BCR. human, and there appear to be epistatic interactions among These inhibitory receptors recognize endogenous ligands. different inhibitory co-receptors. Both mouse Siglec-G and human Siglec-10 recognize 2,6- linked sialic acids, the same glycan ligand as CD22, and also CONCLUSION 2,3-linked sialic acids [92, 101]. PIR-B and its human ho- B lymphocytes express various ITIM-containing recep- mologs LIRB1 and LIRB2 recognize MHC I [102, 103]. tors such as FcRIIB, FCRLs, CD22/Siglec-2, mouse Siglec- PIR-B is shown to bind MHC I in cis [104] as is the case for G/human Siglec-10, CD72, PECAM-1, mouse PD-1 and CD22 interaction to its glycan ligand. CD72 was reported to mouse PIR-B/human LIRB1 and LIRB2. Although some of bind to CD100, a semaphorin expressed in leukocytes in- these molecules contain ITAM-like sequence that can bind to cluding T cells and activated B cells as well as oligodendro- Syk and other signaling molecules upon phosphorylation, cytes in central nervous system [105]. PDL-1 and PDL-2 are overall function of these receptors is negative regulation of ligands for PD-1. PDL1 is expressed in leukocytes such as T BCR signaling by recruiting phosphatases such as SHP-1, and B cells and myeloid cells, and tissues including heart, SHP-2 and SHIPs depending on receptors. Also, these recep- pancreas, brain and muscle, whereas PDL2 expression is tors negatively regulate B cell activation induced by TLR restricted to DCs and macrophages [106, 107]. Although the ligands, although how phosphatases regulates TLR signaling role of these ligands are not yet well understood, these is not yet fully understood. Inhibitory receptors have their ligands may be capable of inducing signal inhibition by co- endogenous ligands. Interaction of these inhibitory co- ligating the inhibitory receptors with BCR, and may also receptors with their ligands may cause co-ligation of the in- play a regulatory role in the signal inhibition mediated by the hibitory receptors with BCR, leading to efficient negative inhibitory receptors either positively or negatively. Indeed, regulation of BCR signaling. For example, immune complex PDL1 and PDL2 are shown to be crucial for signal regula- consisting of IgG and antigen co-ligates FcRIIB and BCR, tion by PD-1 [106, 107], whereas CD100 was proposed to be thereby negatively regulating B cell activation. Alternatively, a negative regulator of CD72 [105]. Ligands may regulate Inhibitory BCR Co-Receptors Infectious Disorders – Drug Targets, 2012, Vol. 12, No. 3 187 ligands regulates the inhibitory activity of these receptors [12] Siriboonrit, U.; Tsuchiya, N.; Sirikong, M.; Kyogoku, C.; independently of co-ligation with BCR, although such regu- Bejrachandra, S.; Suthipinittharm, P.; Luangtrakool, K.; Srinak, D.; Thongpradit, R.; Fujiwara, K.; Chandanayingyong, D.; Tokunaga, lation is not yet well understood. K. Association of Fcgamma receptor IIb and IIIb polymorphisms Polymorphisms of some inhibitory co-receptors such as with susceptibility to systemic lupus erythematosus in Thais. Tissue Antigens, 2003, 61(5), 374-383. Fc RIIB, FCRL3 and CD72 associate with autoimmune dis- [13] Kyogoku, C.; Tsuchiya, N.; Matsuta, K.; Tokunaga, K. Studies on eases including SLE. 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Received: January 31, 2012 Accepted: February 25, 2012