生物
磷酸化
细胞生物学
CD28
蛋白激酶B
PI3K/AKT/mTOR通路
信号转导
T细胞受体
T细胞
免疫学
免疫系统
作者
Richard V. Parry,Jens M. Chemnitz,Kenneth A. Frauwirth,Anthony R. Lanfranco,Inbal Braunstein,Sumire Kobayashi,Peter S. Linsley,Craig B. Thompson,James L. Riley
标识
DOI:10.1128/mcb.25.21.9543-9553.2005
摘要
CTLA-4 and PD-1 are receptors that negatively regulate T-cell activation. Ligation of both CTLA-4 and PD-1 blocked CD3/CD28-mediated upregulation of glucose metabolism and Akt activity, but each accomplished this regulation using separate mechanisms. CTLA-4-mediated inhibition of Akt phosphorylation is sensitive to okadaic acid, providing direct evidence that PP2A plays a prominent role in mediating CTLA-4 suppression of T-cell activation. In contrast, PD-1 signaling inhibits Akt phosphorylation by preventing CD28-mediated activation of phosphatidylinositol 3-kinase (PI3K). The ability of PD-1 to suppress PI3K/AKT activation was dependent upon the immunoreceptor tyrosine-based switch motif located in its cytoplasmic tail, adding further importance to this domain in mediating PD-1 signal transduction. Lastly, PD-1 ligation is more effective in suppressing CD3/CD28-induced changes in the T-cell transcriptional profile, suggesting that differential regulation of PI3K activation by PD-1 and CTLA-4 ligation results in distinct cellular phenotypes. Together, these data suggest that CTLA-4 and PD-1 inhibit T-cell activation through distinct and potentially synergistic mechanisms.
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