Immune responses are exquisitely controlled by signals sensing, integrating and transduction from the surface of the immune cell into the cell. Immunoreceptor tyrosine-based activation motif(ITAM), (in the antagonistic case ITIM, I refers inhibition) is found in the tails of important cell signaling molecules involved in cell signaling transduction especially in immune system, including the T cell receptor complex (CD3 and ζ-chains), the B cell receptor complex (CD79-alpha and -beta chains), and certain Fc receptors. It is a conserved sequence of four amino acids that is repeated twice in the cytoplasmic tails of certain cell surface proteins of the immune system. Y-kinase is required to phosphorylate the tyrosine residues for signal initiation. The receptor molecule then interacts with its ligand and forms a docking site for other proteins involved in the cell signaling pathway.
ITAMs are characterized by a consensus sequence of YxxL/I-(x)6–8-YxxL/I (where x is any amino acid, a tyrosine is separated from a leucine or isoleucine by any two other amino acids, and two of these signatures are typically separated between 6 and 8 amino acids in the tail of the molecule). Most ITIMs contain the consensus sequence (I/V/L/S)xYxx(L/V).
ITAMs are found in multisubunit immunoreceptors such as BCRs (the BCR-associated Igα and Igβ chains), TCRs (the TCR-associated CD3γ, CD3δ, CD3ε, and ζ chains), activating Fc receptors (FcRs, the FcεRI-, the FcγRI-, and the FcγRIII-associated γ chain), DAP12, and several virally encoded transmembrane molecules. The most proximal and essential event in receptor binding is the activation of Src family protein tyrosine kinases (PTKs). Activation of Src family PTKs phosphorylates the tyrosines within ITAM, which, in turn, leads to the recruitment and activation of the tandem SH2 domain–containing Syk and ZAP-70 tyrosine kinases. Src family kinases cause aggregation of ITAM-containing receptors. Dual phosphorylation of the conserved ITAM tyrosines is required to generate a docking site for recruitment and activation of tandem SH2 domains of Syk and/or ZAP-70 kinases. Thereby, multiple downstream pathways are activated which drive activation, proliferation, differentiation and survival. ITAM monophosphorylation also has functional consequence. For example, aggregation-induced monophosphorylation of BCR ITAMs leads to tyrosine phosphorylation of Lyn and a limited number of its downstream substrates consistent with kinase activation. The TCR complex, consisting of a pair of antigen-recognizing chains (αβ or γδ), the CD3 chains (εγ and εδ), and a homodimeric pair of ζ chains, is probably the most thoroughly studied of the ITAM containing-receptors. It contains a total of ten ITAMs, one from each of the CD3 chains and six from the ζ dimer.
Figure 1. A model depicting TCR-mediated ζ chain phosphorylation.
ITIM-containing receptors are evolutionarily conserved membrane proteins, whose cloud is derived from the most primitive metazoa. Specifically, ITAM-containing receptors can result in a decrease or disappearance of cellular responses. Thus, it is increasingly recognized that the attenuation of many immune responses is not simply due to the loss of activating signals but the activation of ITIM containing receptors. It is of great significance to balance between positive and negative signals to determine functional outcomes.
Its inhibitory function was first defined in the low affinity immunoglobulin G (IgG) receptor FcγRIIB. When tyrosine is phosphorylated, it binds to the SH2 domain-containing 5-inositol phosphatase SHIP-1 and SHIP-2 and/or tyrosine phosphatases SHP-1 and SHP-2.
However, recent evidence suggests that incomplete phosphorylation of ITAM tyrosines may alter the output of signaling. For example, the immunoglobulin A (IgA) Fc receptor (FcaRI) initiates a potent inhibition of SHP-1 recruitment, which inhibits cell activation initiated by various heterologous receptors in the absence of antigen without co-aggregation. This explains the function of IgA as an anti-inflammatory isotype. Known as ITAMi, it now describes an increasing number of immune receptors with immune effects.
Figure. 2. Three types of regulation of immune responses by immunoreceptor tyrosine-based activation motifs (ITAM)- or immunoreceptor tyrosine-based inhibitory motif (ITIM)-bearing receptors.
It now appears that the pairing of activating and inhibitory receptors controls the strength and nature of immune responses. Anormalities in ITAM-bearing receptors can result in selective immunodeficiencies and dysfunctional ITIM-bearing receptors can lead to potentially fatal autoimmune disorders. Due to the irreplaceable role of immune signaling pathways, ITIM/ITAM has important role in the treatment of inflammatory and autoimmune diseases and others. Intravenous immunogloblin (IVIG) has been used for many years in the treatment of autoimmune diseases including Kawasaki disease, Guillain–Barre syndrome immune-mediated thrombocytopenia, and many others. It has been reported that ITAMi signaling plays a key role in controlling autologous or heterologous receptors (including TLR4, TNFR, chemokine receptor-2) in inflammatory responses. Anti-FcaRI Fab has been identified as a new potential therapeutic tool to prevent progression of kidney inflammatory diseases..