An immunoreceptor tyrosine-based inhibitory motif (ITIM), is a conserved sequence of amino acids that is found intracellularly in the cytoplasmic domains of many inhibitory receptors of the non-catalytic tyrosine-phosphorylated receptor family found on immune cells. These immune cells include T cells, B cells, NK cells, dendritic cells, macrophages and mast cells. ITIMs have similar structures of S/I/V/LxYxxI/V/L, where x is any amino acid, Y is a tyrosine residue that can be phosphorylated, S is the amino acide Serine, I is the amino acid Isoleucine, and V is the amino acid Valine. ITIMs recruit SH2 domain-containing phosphatases, which inhibit cellular activation. ITIM-containing receptors often serve to target Immunoreceptor tyrosine-based activation motif(ITAM)-containing receptors, resulting in an innate inhibition mechanism within cells. ITIM bearing receptors have important role in regulation of immune system allowing negative regulation at different levels of the immune response. A list of human candidate ITIM-containing proteins has been generated by proteome-wide scans. It has included more than 135 proteins with ITIM motif. This list is reportedly expanded by studying rare human SNPs that create the consensus signature S/I/V/LxYxxI/V/L motif. Structure ITIM motifs are defined as six amino acid signature with the consensus sequence S/I/V/LxYxxL/V, where x stands for any amino acid, Y for a tyrosine residue that can be phosphorylated and S, I, V for amino acids serine, isoleucine, and valine, respectively. ITIM conserved sequence was first identified in the low affinity IgG receptor FcγRIIB. All ITIM containing receptors are a part of the immunoglobulin superfamily. Signaling by ITIM The main characteristic of ITIM-containing molecules is that they become tyrosyl-phopshorylated. In order to become phosphorylated, the inhibitory receptor has to be brought in close proximity to the kinase. This may be achieved by co-crosslinking with an ITAM motif of activating receptor that recruits a Src family kinase. ITIMs place phosphatases near ITAM-containing receptors, allowing phosphatases to dephosphorylate. This results in the deactivation of the signaling pathway of the ITAM-related receptor. Ligand independent phosphorylation of ITIM-bearing molecules may also occur. Phosphorylated ITIM molecules then recruit SH2 domain-containing phosphatases. Four SH2 domain-containing phosphatases have been identified: the two lipid phosphatases SHIP1 and SHIP2 and the two protein tyrosine phosphatases(PTPs) SHP-1 and SHP-2. The dephosphorylation of cell activation critical substrates results due to phosphorylated ITIM's serving as recruitment sites for SHP-1 and SHP-2. The vast majority of ITIM-containing receptors were found to recruit either SHIPs or SHPs. These phosphatases inhibit activation of