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

• Published in: FEBS letters Vol. 574; no. 1; pp. 37 - 41
• Main Authors: Sheppard, Kelly-Ann, Fitz, Lori J., Lee, Julie M., Benander, Christina, George, Judith A., Wooters, Joe, Qiu, Yongchang, Jussif, Jason M., Carter, Laura L., Wood, Clive R., Chaudhary, Divya
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 10-09-2004
• Subjects: CD3ζ ITAM; Immunoinhibition; TCR signaling; ZAP70; TCR signaling; ZAP70; Immunoinhibition; CD3ζ ITAM
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2004.07.083

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.