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The observation that the TCR, BCR, and some Fc receptors are associated with multiple ITAM-signaling subunits suggests that these subunits support the efficient signal amplification upon receptor engagement. Alternatively, the pairing of distinct ITAM-containing subunits could allow activated receptors to link in a modular manner to specific downstream signaling pathways by binding to distinct SH2 domain–containing effector molecules.

Probably the most thoroughly studied of the ITAM containing-receptors is 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 (Figure 1). In total, the TCR complex contains ten ITAMs, one from each of the CD3 chains and six from the ζ dimer. By contrast, other ITAM-containing receptors have two to four ITAMs each. The role of the CD3 and ζ chains in regulating T cell development has been …