T-cell receptor signal transmission: Who gives an ITAM?

T cells have an amazing ability to discern and differentially respond to MHC-embedded peptides that can differ by only a single amino acid. This potential involves a combination of the precise ligand-binding specificities of the T-cell receptor (TCR) and the distinct intracellular signaling processes it transmits. Signaling processes are controlled by the ten immunoreceptor tyrosine-based activation motifs (ITAMs) present in the invariant chains of the TCR complex (TCR ζ and CD3-γ, -δ and -ε). Here, we discuss recent studies of the functions of TCR invariant chains and the contribution of the ten ITAMs to T-cell signal transmission. We incorporate these results into two non-exclusive models of TCR signal transduction: the ITAM multiplicity model, which describes a functional redundancy within the TCR ζ and CD3 ITAMs; and the differential signaling model, which proposes distinct functions for the CD3-γ, -δ and -ε and TCR ζ modules.