Crammed signaling motifs in the T-cell receptor

Although the T cell antigen receptor (TCR) is long known to contain multiple signaling subunits (CD3 gamma, CD3 delta, CD3 epsilon and CD3 zeta), their role in signal transduction is still not well understood. The presence of at least one immunoreceptor tyrosine-based activation motif (ITAM) in each CD3 subunit has led to the idea that the multiplication of such elements essentially serves to amplify signals. However, the evolutionary conservation of non-ITAM sequences suggests that each CD3 subunit is likely to have specific non-redundant roles at some stage of development or in mature T cell function. The CD3 epsilon subunit is paradigmatic because in a relatively short cytoplasmic sequence (similar to 55 amino acids) it contains several docking sites for proteins involved in intracellular trafficking and signaling, proteins whose relevance in T cell activation is slowly starting to be revealed. In this review we will summarize our current knowledge on the signaling effectors that bind directly to the TCR and we will propose a hierarchy in their response to TCR triggering. (C) 2014 Elsevier B.V. All rights reserved.