PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3ζ signalosome and downstream signaling to PKCθ
Abstract
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.
- Publication:
-
FEBS Letters
- Pub Date:
- January 2004
- DOI:
- 10.1016/j.febslet.2004.07.083
- Bibcode:
- 2004FEBSL.574...37S
- Keywords:
-
- TCR signaling;
- CD3ζ ITAM;
- ZAP70;
- Immunoinhibition