PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta

• Published in: FEBS letters Vol. 574; no. 1-3; 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: England 10-09-2004
• Subjects: Amino Acid Sequence; Antigens, CD; Antigens, Surface - chemistry; Antigens, Surface - physiology; Apoptosis Regulatory Proteins; Humans; Isoenzymes - metabolism; Jurkat Cells; Molecular Sequence Data; Phosphorylation; Programmed Cell Death 1 Receptor; Protein Kinase C - metabolism; Protein Kinase C-theta; Protein-Tyrosine Kinases - metabolism; Receptors, Antigen, T-Cell - physiology; Sequence Homology, Amino Acid; Signal Transduction; ZAP-70 Protein-Tyrosine Kinase
• ISSN: 0014-5793

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 CD3zeta. In addition, PD-1 signaling attenuates PKCtheta activation loop phosphorylation in a cognate TCR signal. PKCtheta 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.