Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8(+) T Cell Exhaustion.
Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8(+) T Cell Exhaustion.
复制标题
由抑制性受体PD-1调节的代谢改变引起的生物能量不足是CD8(+) T细胞衰竭的早期驱动因素。
DOI：
10.1016/j.immuni.2016.07.008
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发表时间：
2016-08-16
期刊：
影响因子：
32.4
通讯作者：
Wherry EJ
中科院分区：
文献类型：
--
作者：
Bengsch B;Johnson AL;Kurachi M;Odorizzi PM;Pauken KE;Attanasio J;Stelekati E;McLane LM;Paley MA;Delgoffe GM;Wherry EJ
代谢的动态重编程对于T细胞效应器的功能和记忆的形成是必不可少的。然而，对耗竭的CD8+T(TeX)细胞的代谢调节知之甚少。我们发现，在慢性淋巴细胞性脉络膜脑膜炎病毒(LCMV)感染的第一周，在严重功能障碍出现之前，病毒特异性CD8+T细胞已经无法与急性感染期间产生的效应性T细胞的生物能量相匹配。抑制T细胞生物能量学涉及限制葡萄糖的摄取和使用，尽管雷帕霉素(MTOR)信号的机制靶点持续存在，许多合成代谢途径被上调。PD-1调节早期糖酵解和线粒体的改变，并抑制转录共激活因子pGC-1α。过表达pGC-1α改善生物能量学增强发育中的TeX细胞的功能。通过抗PD-L1在TeX细胞亚群中重新编程代谢来治疗重振活力。这些数据强调了疲劳早期的一个关键代谢控制事件，并表明操纵糖酵解和线粒体代谢可能会增强检查点阻断的结果。在慢性感染和癌症中，耗尽的T细胞逐渐发展为功能低下的效应器，是控制这些疾病的屏障。Wherry和他的同事发现抑制的T细胞代谢是驱动疲劳的早期细胞扰动，并在此过程中涉及PD-1和糖酵解、线粒体和PGC-1α驱动的代谢途径的改变。
Dynamic reprogramming of metabolism is essential for T cell effector function and memory formation. However, the regulation of metabolism in exhausted CD8+ T (Tex) cells is poorly understood. We found that during the first week of chronic lymphocytic choriomeningitis virus (LCMV) infection, before severe dysfunction develops, virus-specific CD8+ T cells were already unable to match the bioenergetics of effector T cells generated during acute infection. Suppression of T cell bioenergetics involved restricted glucose uptake and use, despite persisting mechanistic target of rapamycin (mTOR) signaling and up-regulation of many anabolic pathways. PD-1 regulated early glycolytic and mitochondrial alterations and repressed transcriptional coactivator PGC-1α. Improving bioenergetics by overexpression of PGC-1α enhanced function in developing Tex cells. Therapeutic reinvigoration by anti-PD-L1 reprogrammed metabolism in a subset of Tex cells. These data highlight a key metabolic control event early in exhaustion and suggest that manipulating glycolytic and mitochondrial metabolism may enhance checkpoint blockade outcomes. Exhausted T cells progressively develop poor effector function in chronic infections and cancer and are a barrier controlling these diseases. Wherry and colleagues identify suppressed T cell metabolism as an early cellular perturbation driving exhaustion and implicate PD-1 and altered glycolytic, mitochondrial, and PGC-1α–driven metabolic pathways in the process.