The proline-rich sequence of CD3ε controls T cell antigen receptor expression on and signaling potency in preselection CD4+ CD8+ thymocytes

Antigen recognition by T cell antigen receptors (TCRs) is thought to `unmask' a proline-rich sequence (PRS) present in the CD3 epsilon cytosolic segment, which allows it to trigger T cell activation. Using `knock-in' mice with deletion of the PRS, we demonstrate here that elimination of the CD3e PRS had no effect on mature T cell responsiveness. In contrast, in preselection CD4(+)CD8(+) thymocytes, the CD3 epsilon PRS acted together with the adaptor protein SLAP to promote CD3 zeta degradation, thereby contributing to downregulation of TCR expression on the cell surface. In addition, analysis of CD4(+)CD8(+) thymocytes of TCR-transgenic mice showed that the CD3 epsilon PRS enhanced TCR sensitivity to weak ligands. Our results identify previously unknown functions for the evolutionarily conserved CD3 epsilon PRS at the CD4(+)CD8(+) developmental stage and suggest a rather limited function in mature T cells.