Immunoreceptor tyrosine-based inhibition motifs: a quest in the past and future

Since an immunoreceptor tyrosine-based inhibition motif (ITIM) was first identified in the intracytoplasmic domain of Fc gammaRIIB, ITIMs have been found in a large number of inhibitory molecules that were shown to negatively regulate cell activation. Due to their wide tissue distribution and to the variety of their extracellular ligands, ITIM-containing molecules are involved in the control of a large spectrum of biological functions, mostly but not exclusively related to immunity. On the basis of sequence comparison, ITIMs were structurally defined as 6-amino acid sequences containing a tyrosine (Y) with loosely conserved N-terminal (Y-2) and C-terminal (Y+3) residues. Molecular analysis of signaling events demonstrated that when coaggregated with activating receptors, ITIMs are phosphorylated by Src-family tyrosine kinases, which enables them to recruit Src homology 2 domain-containing phosphatases that antagonize activation signals. Because ITIM-dependent negative regulation seems to be a fundamental regulatory mechanism, both in rodents and in humans, and because it can be used either as a target or as a powerful tool in various diseases, we undertook (i) a genome-wide search of potential novel ITIM-containing molecules in humans, mice, frogs, birds, and flies and (ii) a comparative analysis of potential ITIMs in major animal phyla, from mammals to protozoa. We found a surprisingly high number of potential ITIM-containing molecules, having a great diversity of extracellular domains, and being expressed by a variety of immune and non-immune cells. ITIMs could be traced back to the most primitive metazoa. The genes that encode ITIM-containing molecules that belong to the immunoglobulin superfamily or to the C-lectin family seem to derive from a common set of ancestor genes and to have dramatically expanded and diverged in Gnathostomata (from fish to mammals).