ITIM

ITIM is the acronym for "immunoreceptor tyrosine-based inhibitory motif". ITIM consists of a conserved sequence of six amino acids: I/V/L/SxYxxI/L/V. Here, the first amino acid is either an isoleucine, valine, leucine or serine followed by any amino acid with subsequent tyrosine separated by two more arbitrary amino acids from an isoleucine, leucine or valine. ITIM is found in the cytoplasmic domains of many inhibitory receptors of the non-catalytic tyrosine phosphorylated receptor family on immune cells. These include T cells , B cells , NK cells , dendritic cells , macrophages and mast cells.

Binding of a specific ligand to the receptor causes phosphorylation of tyrosine residues in the ITIM by Src family kinases. Subsequently, Src homology 2-containing protein tyrosine phosphatases (SHP) such as SHP-1, SHP-β or the Src homology 2-containing inositol-5-phosphatase (SHIP) are recruited to the phosphorylated ITIM. These lead to the dephosphorylation of activating receptors and molecules and thus exert an inhibitory effect on the cell by inhibiting the activating signal transduction chain. A modification of the classical ITIM is the immunoreceptor tyrosine-based switch motif (ITSM). In this signal transduction motif, the first amino acid of the consensus sequence of the ITIM is replaced by a threonine (TxYxxI/V). However, in contrast to the ITIM, the alternating motif can recruit adapter molecules that induce activating signal transduction as well as those that initiate an inhibitory signal transduction cascade. Depending on the intracellular, physiological conditions, the ITSM thus enables a switch between activating and inhibitory signaling.

1. Coxon CH et al. (2017) ITIM receptors: more than just inhibitors of platelet activation. Blood. 129:3407-3418.