The proline-rich sequence of CD3ε as an amplifier of low-avidity TCR signaling

Engagement of peptide-MHC by the TCR induces a conformational change in CME that exposes a proline-rich sequence (PRS) and recruits the cytoskeletal adaptor Nck. This event, which precedes phosphorylation of the CD3 epsilon ITAM, has been implicated in synapse formation and T cell function. However, there is compelling evidence that responsiveness to TCR ligation is CME PRS independent. In this study, we show that the CD3 epsilon PRS is necessary for peptide-MHC-induced phosphorylation of CD3 epsilon and for recruitment of protein kinase C theta to the immune synapse in differentiated CD8(+) T lymphocytes. However, whereas these two events are dispensable for functional T cell responsiveness to high-avidity ligands, they are required for responsiveness to low-avidity ones. Thus, in at least certain T cell clonotypes, the CD3 epsilon PRS amplifies weak TCR signals by promoting synapse formation and CD3 epsilon phosphorylation.