On the Control of TCR Phosphorylation.

The T-cell receptor (TCR) is responsible first of all for recognizing small peptides embedded in major histocompatibility complex molecules (pMHC). The information that a complex has thus formed is then transduced across the membrane via “triggering” of the TCR. This results in a net increase in the number and/or half-life of phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) present in the CD3 subunits of the TCR (Smith-Garvin et al., 2009). Signaling via tyrosine-containing motifs phosphorylated by Src tyrosine kinases is not unique to the TCR complex; in fact, a large number of receptors present in lymphocytes likely signal in the same manner (Davis and van der Merwe, 2006). Almost 30 years after the TCR was discovered, however, the regulation of its phosphorylation remains poorly understood. An important recent development is that relatively high levels of active forms of the Src kinase Lck are present in resting T-cells (Nika et al., 2010), prompting the question: why are T cells not constitutively activated? Drawing on recently published and unpublished work on the TCR and, in particular, the extensive literature on the regulation of Src kinases, in this Opinion article we discuss how TCR phosphorylation might be controlled in T cells. We consider how, at a global level, the homeostatic balancing of tyrosine kinase and phosphatase expression levels might keep TCR phosphorylation under tonic control, and how a previously overlooked mechanism of Src kinase activation might contribute to ultra-sensitive signaling in T cells, helping to locally counteract these global homeostatic effects. Rather than emphasizing its unconventionality, we highlight ways in which TCR behavior likely resonates with known molecular and cellular processes. As discussed previously (James et al., 2007, 2011), we assume that the “resting” TCR is monovalent. TCR triggering per se is also considered elsewhere (Davis and van der Merwe, 1996, 2006).