Biology of Immunoreceptor Tyrosine-based Inhibition Motif-Bearing Molecules

Abstract

The term “immunoreceptor tyrosine-based inhibition motif” (ITIM) was coined after the term “immunoreceptor tyrosine-based activation motif” (ITAM) to designate molecular motifs that antagonize ITAM-dependent cell activation (Daëron et al. 1995a; D’Ambrosio et al. 1995). The concept of ITIM lies on the coexpression by single cells of “on” and “off” molecules which, when kept in close proximity, transduce intracellular signals that interfere with each other. On and off receptors can be constitutively associated at the cell membrane, such as B Cell receptors (BCR) and CD22 on B lymphocytes (Law et al. 1996) or high-affinity IgE receptors (FcɛRI) and mast cell-associated function antigen (MAFA) on mast cells (Guthmann et al. 1995); or they can be coaggregated by extracellular ligands. Thus, ITIM-bearing low-affinity receptors for IgG (FcγRIIB) and ITAM-bearing receptors are coaggregated by IgG antibodies or soluble immune complexes (Amigorena et al. 1992; Daëron et al. 1995b; Daëron et al. 1995a). Although the spatial relationship established between MHC class I-specific killer cell Ig-like receptors (KIRs) and receptors that trigger cytotoxicity (Moretta et al. 1997) is unclear, KIRs needed to be coligated with FcɛRI by the same soluble molecules in order to inhibit the activation of mast cells in a reconstitution model (Bléry et al. 1997). Following aggregation or coaggregation of the receptors, both ITAMs and ITIMs are tyrosyl phosphorylated by src family protein tyrosine kinases and, once phosphorylated, they recruit cytoplasmic molecules having SH2 domains (Cambier 1995; Burshtyn and Long 1997; Vivier and Daëron 1997).