The role of CD22 and other inhibitory co-receptors in B-cell activation

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Inhibitory co-receptors downmodulate B-cell receptor (BCR) signalling by setting a signalling threshold that prevents overstimulation of B cells. Activation of these inhibitory co-receptors occurs by phosphorylation on their cytoplasmic inhibitory immunoreceptor tyrosine-based inhibition motifs (ITIMs), followed by recruitment of the tyrosine phosphatase SHP-1 or the lipid phosphatase SHIP, and depends on their association with the BCR. Recent evidence shows that B-cell signal inhibition is regulated by ligand binding of inhibitory receptors.

Introduction

When B cells interact with antigens, transmembrane signal transduction takes place through the B cell antigen receptor (BCR), leading to modulation of gene expression, resulting in activation, anergy or apoptosis of B cells. Accessory co-receptors expressed on the B-cell surface modulate BCR signalling either positively or negatively. These co-receptors include the low-affinity receptor for IgG (FcγRII), CD22 and CD72, which negatively regulate BCR signalling and are thus called inhibitory BCR co-receptors. Inhibitory co-receptors set the BCR signalling threshold and thereby prevent overstimulation of the B cells. These inhibitory co-receptors contain immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the cytoplasmic tails. When phosphorylated, ITIMs recruit inhibitory intracellular signalling proteins, including protein tyrosine phosphatases (SH2-domain-containing protein tyrosine phosphatase-1 [SHP-1] and SHP-2) and the lipid phosphatase SH2-domain-containing inositol phosphatase (SHIP). These phosphatases counteract the BCR-induced activation signalling cascades that are mediated by phosphorylation of various signalling molecules. Phosphorylation of the ITIMs in these co-receptors occurs only when the co-receptors associate with the BCR.

New evidence suggests that BCR association of inhibitory receptors is a process that is regulated by ligand binding. The mechanisms of inhibition by various mouse inhibitory receptors are discussed in this review, with some emphasis on CD22.

Section snippets

Inhibition of B cell signalling by CD22

CD22 is a 140 kDa type I membrane protein and is a member of the Siglec (sialic-acid-binding immunoglobulin-like lectin) family, a family of inhibitory adhesion receptors expressed on leukocytes. CD22 is expressed in a B-cell lineage specific fashion, starting at the pre-B cell stage. CD22 has seven immunoglobulin (Ig)-like extracellular domains and a cytoplasmic tail containing six tyrosines, three of which belong to the ITIM sequences.

Inhibition of B cell signalling by CD72

CD72 is a type II transmembrane protein of the C-type lectin family. CD72 is expressed primarily on B cells, but also on dendritic cells (DCs), macrophages and subpopulations of T cells. CD72 contains an ITIM and an ITIM-like sequence in the cytoplasmic part. It has been shown that crosslinking of the BCR induces phosphorylation of tyrosines on CD72, resulting in its association with SHP-1 [28, 29, 30]. However, direct association of CD72 with the BCR has not been demonstrated so far. Tyrosine

Function of the inhibitory protein PIR-B on B cells

Mice express the paired immunoglobulin-like receptors (PIRs) PIR-A and PIR-B, which are proposed to be orthologues of the human leukocyte immunoglobulin-like receptors (LILRs or LIRs; also called immunoglobulin-like transcript [ILT] or myeloid immunoglobulin-like receptors [MIRs]) on the basis of structural similarity, similar expression profiles and genomic location. PIR-A and PIR-B are expressed on myeloid cells and B cells. Whereas PIR-A is a protein family encoded by multiple genes, PIR-B

Inhibition of B cell signalling by FcγRIIB

IgG immune complexes were recognized as potent inhibitory ligands for B cells a long time ago. The low-affinity IgG receptor FcγRIIB, the only IgG Fc receptor expressed on B cells, carries a cytoplasmic ITIM motif and is inhibitory. IgG immune complexes can co-ligate the FcγRIIB to the BCR. This co-ligation leads to inhibition of BCR-induced Ca2+ signals and cellular proliferation [46]. Phosphorylation of the FcγRIIB ITIM motif is required for the inhibition, and inhibition depends on binding

Conclusions

In summary, B cells constitutively express a set of inhibitory co-receptors, which are regulated by surprisingly different mechanisms. Generally, inhibition relies on the presence of ITIM motifs and on recruitment of either SHP-1 or SHIP to this motif. The phosphorylation of ITIMs on inhibitory co-receptors depends on their association with the BCR, either constitutively or induced, as has been shown for CD22 and FcγRIIB. This direct association still needs to be demonstrated for CD72 and

Update

Interesting recent work showed that restoration of FcγRIIB levels in lupus-prone mouse strains, which have naturally diminished levels, is sufficient to prevent autoimmunity [59]. Also, a new family of Fc receptor relatives, which is expressed on B cells, has been characterized in human and mouse [60].

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work is supported by the Deutsche Forschungsgemeinschaft and Wilhelm-Sanderstiftung.

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