ITAMs

ITAMs, or immunoreceptor tyrosine-based activation motifs, are conserved amino acid sequences in the cytoplasmic tails of several immune receptor subunits. A canonical ITAM sequence is YxxL/I-(X)6-8-YxxL/I, containing two tyrosines that can be phosphorylated.

ITAMs are found in adaptor chains and receptor subunits such as CD3ζ, CD3ε, CD3δ, CD3γ of the T cell receptor complex; CD79a and CD79b of the B cell receptor; Fc receptor gamma chain (FcRγ) and DAP12 that pair with various NK and myeloid receptors.

Upon receptor engagement, Src-family kinases (e.g., Lck, Fyn) phosphorylate the tyrosines in ITAMs. The phosphotyrosines recruit SH2-domain kinases such as ZAP-70 in T cells and Syk in B cells, initiating signaling cascades involving PLCγ1, calcium release, PKC, MAP kinases, and NF-κB, culminating in lymphocyte activation and cytokine production.

ITAMs operate as a key activation module; their function may require receptor clustering or dimerization; some receptors possess a single YxxL/I motif termed a hemITAM, which can activate only when dimerized.

Regulation of ITAM signaling involves phosphatases and negative regulators, while inhibitory receptors often use ITIMs (tyrosine-based inhibitory motifs) to dampen ITAM signaling, maintaining immune balance.

Clinical and research relevance: ITAM signaling is central to adaptive immunity and is a focus in immunodeficiency research, autoimmunity, and cancer immunotherapy. In CAR-T cells, signaling domains derived from ITAM-containing adaptors like CD3ζ contribute to T cell activation upon antigen recognition.