Selective expansion of a subset of exhausted CD8 T cells by αPD-L1 blockade
Selective expansion of a subset of exhausted CD8 T cells by αPD-L1 blockade
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DOI：
10.1073/pnas.0801497105
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发表时间：
2008-09-30
影响因子：
11.1
通讯作者：
Wherry, E. John
中科院分区：
文献类型：
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作者：
Blackburn, Shawn D.;Shin, Haina;Wherry, E. John
程序性死亡-1 （PD-1）在慢性感染过程中调节T细胞衰竭。阻断PD-1: pd -配体（PD-L）通路可使衰竭的CD8 T细胞重新活化。然而，阻断PD-1: PD-L相互作用究竟如何改善T细胞免疫仍不清楚。PD-1: PD-L阻断可以将所有耗尽的T细胞重新编程为抗病毒效应器。或者，这种阻断可能选择性地扩大一个耗尽的T细胞亚群。我们在小鼠慢性病毒感染过程中发现了两个耗尽的CD8 T细胞亚群。耗尽的CD8 T细胞的一个亚群被α PD-L1阻断所拯救，而另一个亚群则表现出更多的终末分化，并且对PD-1: PD-L阻断反应较差。阻断PD-1: PD-L相互作用可减少自发凋亡，增强可拯救亚群的扩增和保护性免疫，但对衰竭CD8 T细胞的晚期分化亚群无效。这些结果对预测基于pd -1的治疗干预的临床反应和理解持续感染期间的T细胞动力学具有重要意义。
Programmed death-1 (PD-1) regulates T cell exhaustion during chronic infections. Blocking the PD-1: PD-ligand (PD-L) pathway reinvigorates exhausted CD8 T cells. Exactly how blocking PD-1: PD-L interactions improves T cell immunity, however, remains unclear. PD-1: PD-L blockade could reprogram all exhausted T cells to become antiviral effectors. Alternatively, this blockade might selectively expand a subset of exhausted T cells. We have identified two subpopulations of exhausted CD8 T cells during chronic viral infection in mice. One subset of exhausted CD8 T cells is rescued by alpha PD-L1 blockade, whereas the other subset appears more terminally differentiated and responds poorly to PD-1: PD-L blockade. Blocking PD-1: PD-L interactions reduces spontaneous apoptosis and enhances expansion and protective immunity of the rescuable subset, but not the more terminally differentiated subset of exhausted CD8 T cells. These results have implications for predicting clinical responses to PD-1-based therapeutic interventions and for understanding T cell dynamics during persisting infections.