PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta.
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.
Sheppard
Kelly-Ann
KA
Inflammation Department, Wyeth Research, 87 Cambridge Park Drive, Cambridge, MA 02140, USA.
Fitz
Lori J
LJ
Lee
Julie M
JM
Benander
Christina
C
George
Judith A
JA
Wooters
Joe
J
Qiu
Yongchang
Y
Jussif
Jason M
JM
Carter
Laura L
LL
Wood
Clive R
CR
Chaudhary
Divya
D
D000595:Amino Acid Sequence; D015703:Antigens, CD; D000954:Antigens, Surface / Q000737:chemistry / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D010766:Phosphorylation; D061026:Programmed Cell Death 1 Receptor; D011493:Protein Kinase C / Q000378:metabolism*; D000074121:Protein Kinase C-theta; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D051746:ZAP-70 Protein-Tyrosine Kinase
D015703:Antigens, CD; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D007527:Isoenzymes; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta