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 firmly established, and we recommend the recent review by Love and Shores (9) on this subject. To explore the role of these ITAMs in TCR function, several groups have transduced ζ chains lacking one or more of these sequences into TCR transgenic, ζ chain–deficient mice. In all cases, it appears that peripheral T cells from the ζ chain–reconstituted animals can still be activated through the TCR (reviewed in refs. 9, 10), suggesting that ITAMs present in the CD3 chains are sufficient for this process. Indeed, different CD3 chain ITAMs have been found to interact with distinct substrates in vitro (reviewed in ref. 6), implying that there is some potential for activating distinct signaling cascades through these various motifs. Thus, as Sommers et al. have noted, ITAM-mutant CD3ε subunits placed into CD3ε-deficient mice do not support T cell survival as the wild-type subunit does, at least in the transgenic TCR mouse line studied (11). These authors also found that T cell maturation appeared normal, suggesting that, as was seen in ζ chain ITAM-deficient animals, the loss of a functional CD3ε ITAM leads to a quantitative but not a qualitative effect on TCR signaling (11). A recent study has shown that in T cells from CD3δ-deficient mice, which fail to undergo normal positive selection, TCR-induced ζ chain phosphorylation within lipid raft fractions and extracellular signal–regulated kinase (ERK) activation are defective. Interestingly, both events can be reconstituted following introduction of a CD3δ subunit lacking not just its ITAM but its entire cytoplasmic domain (12). Consistent with this finding, mutation of a TCRα domain required for association with CD3δ blocks positive selection (7). Therefore, in addition to their contribution to TCR signaling, the CD3 subunits may also act through non-ITAM domains to detect or influence TCR conformational changes occurring during ligand binding.