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Critical Reviews™ in Immunology
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ISSN Print: 1040-8401
ISSN Online: 2162-6472

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Critical Reviews™ in Immunology

DOI: 10.1615/CritRevImmunol.v18.i6.30
pages 525-544

FcR-Mediated Inhibition of Cell Activation and Other Forms of Coinhibition

Colin C. Anderson
Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada, N6A 5C1
Nicholas R. StC. Sinclair
Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada, N6A 5C1

ABSTRACT

The tripartite inactivation model proposed that coaggregation of the B cell antigen receptor (BCR) with the Fc receptor (FcR) by antigen and specific IgG antibody complexes explained the Fc-dependent inhibition of immune responses by antibody. This model has since been substantiated by many observations and its impact on studies of immune regulation has been threefold: (1) IgG antibody, via FcγRIIB, mediates inhibition of cell activation in many cell types, demonstrating the general importance of this mechanism in immune regulation; (2) FcγRIIB was the first receptor described that regulates immune responses by coinhibition, that is, regulation as a result of interaction between activating receptors (BCR, TCR, FcεRI, FcγRIII, FcγRIIA) and inhibitory receptors (FcγRIIB, CTLA4, CD5, CD22, p58/70/140 KIR, gp49Bl/gp91, Ly49A/C/E/F/G, NKG2-A/B, APCR, Fas (CD95), TGFβ-R, TNF-R, IFNγ-R, and others). The list of coinhibitors is expanding, just as the list of costimulators has grown. Tolerance through multiple coinhibitors implies that Signal 1 alone is not tolerogenic; and (3) Studies of FcγRIIB coinhibitory mechanisms have pointed the way to potential general inhibitory signaling pathways used by many receptors, involving the competing effects of various kinases and phosphatases, and other competitive events. Investigations of FcγRIIB physiologic function and of other coinhibitory receptors, together with recent biochemical analyses, give an initial understanding of the biology of these inhibitory receptors. Paradoxes within and between theoretical constructs, functional observations, and mechanistic studies point to critical questions for future study.