CD22: an inhibitory enigma

Abstract

CD22 is an inhibitory coreceptor of the B-cell receptor (BCR), and plays a critical role in establishing signalling thresholds for B-cell activation. Like other coreceptors, the ability of CD22 to modulate B-cell signalling is critically dependent upon its proximity to the BCR, and this in turn is governed by the binding of its extracellular domain to alpha2,6-linked sialic acid ligands. Manipulation of CD22 ligand binding in various experimental settings has profound effects on B-cell signalling, but as yet there is no complete model for how ligand binding in vivo controls normal CD22 function. Several elegant studies have recently shed light on this issue, although the results appear to suggest two mutually exclusive models for the role of ligand binding; in either promoting or inhibiting, CD22 function. We shall therefore discuss these results in detail, and suggest possible approaches by which these conflicting experimental findings might be reconciled. We shall also consider a second important issue in CD22 biology, which relates to the role that defects in this receptor might play in mediating autoimmune disease. We review the current evidence for this, and discuss the importance of genetic background in modifying CD22 function and predisposition to autoimmunity.

Figure 1

Upon B-cell receptor (BCR) cross-linking and translocation to lipid rafts, Lyn phosphorylates the immunoreceptor tyrosine-based activation motif tyrosine residues of immunoglobulin α/β. This creates docking sites for other protein tyrosine kinase such as Syk, which in turn phosphorylate and recruit the adaptor molecule BLNK (B-cell linker protein). BLNK forms a scaffold for the association of numerous signalling components, including Vav-1, BTK and phospholipase Cγ2 (PLCγ2). Many of these proteins also contain pleckstrin homology domains, and are stabilized in this complex by interaction with the phospholipid PI(3,4,5)P₃ [produced by phosphoinositide 3-kinase (PI3K)]. Calcium induction upon BCR ligation is brought about by PLCγ2, which converts PI(4,5)P₂ to I(1,4,5)P₃ (IP₃) and diacylglycerol (DAG). IP₃ promotes calcium release from intracellular stores, which in turn triggers an influx of calcium through the opening of Ca²⁺-release-activated channels (CRACs), and activation of the nuclear factor κB, nuclear factor of activated T cells and extracellular signal-regulated kinase signalling pathways. Calcium efflux is mediated by the plasma membrane Ca²⁺-ATPase (PMCA4). CD22 serves to inhibit the BCR signal at several points in this signalling cascade. Following phosphorylation of its immunoreceptor tyrosine-based inhibitory motif residues by Lyn, CD22 provides a docking site for the recruitment of SHP-1. SHP-1 acts to dephosphorylate and inactivate Vav-1, BLNK and CD19 (accompanied by a reduction in PI3K activity) to effect a dampening of the BCR signal. SHP-1 also promotes calcium efflux through activation of PMCA4.

Figure 2

(a) Studies in ligand-deficient mice suggest that CD22 is normally sequestered away from the B-cell receptor (BCR) in clathrin-rich domains (i). Sequestration is mediated by homotypic interactions with other CD22 molecules, via α2,6-linked sialic acid (α2,6Sia) binding. In the absence of ligand, CD22 is released from these constraints, resulting in greater association with the BCR and suppression of signalling (ii). (b) Studies in gene-targeted mice (that express CD22 that cannot bind ligand) suggest that CD22 normally makes α2,6Sia-dependent contacts with the BCR (or other BCR-associated proteins) to mediate signal inhibition (iii). When ligand binding is precluded, CD22 cannot interact with the BCR, and the BCR signal is not effectively inhibited (iv).