CD22: an inhibitory enigma

Abstract

CD22: an inhibitory enigma Introduction CD22 is an inhibitory coreceptor of the B-cell receptor (BCR) and, like other coreceptors, is required to modu- late the antigen receptor signal in response to cues from the local microenvironment.1 This is essential to ensure that an appropriate humoral response is mounted against pathogens, but that reactivity to self antigens and auto- immunity is avoided.2–4 To fine-tune the BCR signal, and to integrate an extensive variety of environmental signals, B cells express a broad repertoire of activatory and inhibi- tory coreceptors on their surface.5,6 These molecules pos- sess immunoreceptor tyrosine-based activation (ITAM) and inhibition (ITIM) motifs in their intracellular domains, which serve as scaffolds to recruit signalling molecules that either augment or inhibit the BCR signal. The extent to which these receptors are associated with the BCR, and hence their capacity to modulate its signal, is governed by the interactions of their extracellular domains with as yet incompletely defined sets of ligands. These ligands can exist in cis on the same cell surface, in trans on adjacent cell surfaces, in a soluble form, or bound to cell-associated antigen, for example immuno- globulin G (IgG) in the case of FccRIIb (CD32b),7 or complement in the case of the CD21/CD19 coreceptor complex.2 CD22 was originally identified as a B-cell-associated adhesion protein that appeared to function in the regula- tion of B-cell activation.8–13 It is a member of the sialic acid-binding immunoglobulin-like lectin (Siglec) family of adhesion molecules,14 and binds specifically to glycans that possess sialic acid, attached in a2,6-linkage to an underlying b1,4-linked galactose residue (a2,6Sia).15,16 This is a common structure on N-linked glycans and is abundantly expressed on the surface of many cells, including erythrocytes, monocytes, cytokine-activated endothelial cells, T cells and B cells.17–19 In addition, a2,6Sia residues are present on some sol