Organization of Proximal Signal Initiation at the TCR:CD3 Complex

The series of events leading to T-cell activation following antigen recognition has been extensively investigated. Although the exact mechanisms of ligand binding and transmission of this extracellular interaction into a productive intracellular signaling sequence remains incomplete, it has been known for many years that the immunoreceptor tyrosine activation motifs (ITAMs) of the T-cell receptor (TCR):CD3 complex are required for initiation of this signaling cascade because of the recruitment and activation of multiple protein tyrosine kinases, signaling intermediates, and adapter molecules. It however remains unclear why the TCR:CD3 complex requires 10 ITAMs, while many other ITAM-containing immune receptors, such as Fc receptors (FcRs) and the B cell receptor (BCR), contain far fewer ITAMs. We have recently demonstrated that various parameters of T cell development and activation are influenced by the number, as well as location and type, of ITAMs within the TCR:CD3 complex and hence propose that the TCR is capable of 'scalable signaling' that facilitates the initiation and orchestration of diverse T-cell functions. While many of the underlying mechanisms remain hypothetical, this review intends to amalgamate what we have learned from conventional biochemical analyses regarding initiation and diversification of T-cell signaling, with more recent evidence from molecular and fluorescent microscopic analyses, to propose a broader purpose for the TCR:CD3 ITAMs. Rather than simply signal initiation, individual ITAMs may also be responsible for the differential recruitment of signaling and regulatory molecules which ultimately affects T-cell development, activation and differentiation.