期刊
IMMUNITY
卷 45, 期 2, 页码 358-373出版社
CELL PRESS
DOI: 10.1016/j.immuni.2016.07.008
关键词
-
类别
资金
- German Research Foundation fellowship [BE5496/1-1]
- Sidney Kimmel Foundation for Cancer Research [SKF-015-039]
- Samuel and Emma Winters Foundation
- NIH (Skin Cancer SPORE) [P50CA121973]
- Robertson Foundation/Cancer Research Institute Irvington Fellowship
- Philadelphia Foundation's Brody Family Medical Trust Fund fellowship
- NIH [AI105343, AI082630, AI095608, AI112521, AI115712, AI117718, AI108545, AI2010085]
- Parker Institute for Cancer Immunotherapy
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 upregulation of many anabolic pathways. PD-1 regulated early glycolytic and mitochondrial alterations and repressed transcriptional coactivator PGC-1 alpha. Improving bioenergetics by overexpression of PGC-1 alpha 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 might enhance checkpoint blockade outcomes.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据