ITAM-mediated signaling by the T-cell antigen receptor

Abstract

Signal transduction by the T-cell antigen receptor (TCR) is initiated by phosphorylation of conserved motifs (ITAMs) contained within the cytoplasmic domains of the invariant subunits. TCR complexes contain a total of 10 ITAMs and this unusual configuration has prompted studies of the role of specific ITAMs, or of ITAM multiplicity, in regulating TCR-directed developmental and effector responses. Here, we summarize data generated during the past two decades and discuss how these findings have in some cases resolved, and in others complicated, outstanding questions relating to the function of TCR ITAMs.

Figure 1.

ITAM-containing proteins. Murine ITAM sequences were obtained from GenBank. Amino acids that align with the consensus ITAM sequence are shown in blue.

Figure 2.

Comparison of the ITAM-containing T- and B-cell antigen receptors, Fc receptors and NK receptors. Subunit composition of the T-cell antigen receptor (TCR), B-cell antigen receptor (BCR), FcεR1 (an example of an activating Fc receptor) and Ly49 (an example of an activating NK receptor). Blue rectangles represent ITAMs.

Figure 3.

Proximal signaling events in the TCR-coupled signaling pathway. Interactions between the TCR and peptide-MHC results in the activation of Lck, a member of the Src family of tyrosine kinases. Lck then phosphorylates the two-tyrosine residues within the ITAMs of the CD3 and ζ chains. A second tyrosine kinase, ZAP-70, is specifically recruited to biphosphorylated ITAMs. Phosphorylation of ZAP-70 by Lck results in its activation. ZAP-70 and Lck phosphorylate and activate several downstream target proteins eventually leading to Ras activation, calcium mobilization, and actin cytoskeleton rearrangements, and ultimately to the activation of transcription factors.