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

Summary: Since an immunoreceptor tyrosine‐based inhibition motif (ITIM) was first identified in the intracytoplasmic domain of FcγRIIB, 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).