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
Inflammation Department, Wyeth Research, 87 Cambridge Park Drive, Cambridge, MA 02140, USA.
FEBS Lett. 2004 Sep 10;574(1-3):37-41. 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 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.
免疫抑制受体程序性死亡-1（PD-1）的激活会减弱T细胞受体（TCR）介导的白细胞介素-2（IL-2）产生及T细胞增殖的激活。在此，我们证明PD-1对T细胞功能的调节涉及抑制TCR介导的ζ链相关蛋白激酶70（ZAP70）磷酸化以及与CD3ζ的结合。此外，PD-1信号传导会减弱同源TCR信号中蛋白激酶Cθ（PKCθ）激活环的磷酸化。PKCθ已被证明是T细胞产生IL-2所必需的。一种磷酸化的PD-1肽，对应于C末端免疫受体酪氨酸转换基序（ITSM），在体外作为含Src同源2结构域蛋白磷酸酶-2（SHP-2）和含Src同源2结构域蛋白磷酸酶-1（SHP-1）的停靠位点，而含有N末端PD-1免疫受体酪氨酸抑制基序（ITIM）的磷酸化肽仅与SHP-2结合。
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