PD‐1 inhibits T‐cell receptor induced phosphorylation of the ZAP70/CD3ζ signalosome and downstream signaling to PKCθ

Engagement of the immunoinhibitory receptor, programmed death‐1 (PD‐1) attenuates T‐cell receptor (TCR)‐mediated activation of IL‐2 production and T‐cell proliferation. Here, we demonstrate that PD‐1 modulation of T‐cell function involves inhibition of TCR‐mediated phosphorylation of ZAP70 and association with CD3ζ. In addition, PD‐1 signaling attenuates PKCθ activation loop phosphorylation in a cognate TCR signal. PKCθ has been shown to be required for T‐cell IL‐2 production. A phosphorylated PD‐1 peptide, corresponding to the C‐terminal immunoreceptor tyrosine‐switch motif (ITSM), acts as a docking site in vitro for both SHP‐2 and SHP‐1, while the phosphorylated peptide containing the N‐terminal PD‐1 immunoreceptor tyrosine based inhibitory motif (ITIM) associates only with SHP‐2.