Ligand Recognition Determines the Role of Inhibitory B Cell Co-receptors in the Regulation of B Cell Homeostasis and Autoimmunity

Abstract

B cells express various inhibitory co-receptors including CD22, CD72, and Siglec-G. These receptors contain immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the cytoplasmic region. Although many of the inhibitory co-receptors negatively regulate BCR signaling by activating SH2-containing protein tyrosine phosphatase 1 (SHP-1), different inhibitory co-receptors have distinct functional properties. CD22, Siglec-G, and CD72 preferentially regulate tonic signaling in conventional B cells, B-1 cell homeostasis, and development of lupus-like disease, respectively. CD72 recognizes RNA-related lupus self-antigen Sm/RNP as a ligand. This ligand recognition recruits CD72 to BCR in Sm/RNP-reactive B cells thereby suppressing production of anti-Sm/RNP autoantibody involved in the pathogenesis of lupus. In contrast, Siglec-G recognizes α2,3 as well as α2,6 sialic acids whereas CD22 recognizes α2,6 sialic acid alone. Because glycoproteins including BCR are dominantly glycosylated with α2,3 sialic acids in B-1 cells, Siglec-G but not CD22 recruits BCR as a ligand specifically in B-1 cells, and regulates B-1 cell homeostasis by suppressing BCR signaling in B-1 cells. Thus, recognition of distinct ligands determines functional properties of different inhibitory B cell co-receptors.

Keywords: B-1 cells; CD22; CD72; Sm/RNP; inhibitory B cell co-receptor; sialic acid; siglec-G; systemic lupus erythematosus.

Figure 1

Differential functional properties of inhibitory B cell co-receptors. Mouse B cells express various inhibitory co-receptors such as CD72, CD22, Siglec-G, PIR-B, PEACAM1, PD-1, and FcγRIIB. These receptors contain ITIMs in the cytoplasmic region and recruit SH2-containing phosphatases such as SHP-1, SHP-2, and SHIP-1 upon phosphorylation by Lyn, leading to down-modulation of BCR signaling. Although many of these inhibitory receptors activate SHP-1, CD72, CD22, and Siglec-G inhibits development of lupus-like disease, high tonic signaling phenotypes of conventional B cells, and B-1 cell expansion, respectively.

Figure 2

Ligand recognition determines the functional properties of CD72 and Siglec-G. (A,B) CD72 specifically inhibits BCR signaling in Sm/RNP-reactive B cells by recognizing Sm/RNP as a ligand. When Sm/RNP interacts with Sm/RNP-reactive BCR, CD72 is recruited to BCR by recognition of Sm/RNP (A). CD72 ITIM is then phosphorylated by Lyn and recruits SHP-1. This leads to suppression of BCR signaling in Sm/RNP-reactive B cells thereby inhibiting production of anti-Sm/RNP antibody crucial for development of lupus. When other antigens that do not bind to CD72 interact with BCR, CD72 is kept away from BCR and does not inhibit BCR signaling (B). (C) Siglec-G inhibits BCR signaling in B-1 cells by recognizing α2,3 sialic acid as a ligand. Because glycoproteins in B-1 cells are dominantly glycosylated with α2,3 sialic acid, Siglec-G constitutively associates with BCR by recognizing α2,3 sialic acid expressed on BCR in B-1 cells, thereby down-modulating BCR signaling (35). CD22 does not regulate BCR signaling in B-1 cells because CD22 recognizes α2,6 sialic acid but not α2,3 sialic acid.