氧化磷酸化
细胞生物学
T细胞
细胞生长
氧化应激
细胞毒性T细胞
线粒体
干细胞
下调和上调
祖细胞
刺激
生物
磷酸化
免疫学
免疫系统
生物化学
体外
内分泌学
基因
作者
Santosha A. Vardhana,Madeline A. Hwee,Mirela Berisa,Daniel K. Wells,Kathryn E. Yost,Bryan King,Melody Smith,Pamela S. Herrera,Howard Y. Chang,Ansuman T. Satpathy,Marcel R.M. van den Brink,Justin R. Cross,Craig B. Thompson
出处
期刊:Nature Immunology
[Springer Nature]
日期:2020-07-13
卷期号:21 (9): 1022-1033
被引量:244
标识
DOI:10.1038/s41590-020-0725-2
摘要
The majority of tumor-infiltrating T cells exhibit a terminally exhausted phenotype, marked by a loss of self-renewal capacity. How repetitive antigenic stimulation impairs T cell self-renewal remains poorly defined. Here, we show that persistent antigenic stimulation impaired ADP-coupled oxidative phosphorylation. The resultant bioenergetic compromise blocked proliferation by limiting nucleotide triphosphate synthesis. Inhibition of mitochondrial oxidative phosphorylation in activated T cells was sufficient to suppress proliferation and upregulate genes linked to T cell exhaustion. Conversely, prevention of mitochondrial oxidative stress during chronic T cell stimulation allowed sustained T cell proliferation and induced genes associated with stem-like progenitor T cells. As a result, antioxidant treatment enhanced the anti-tumor efficacy of chronically stimulated T cells. These data reveal that loss of ATP production through oxidative phosphorylation limits T cell proliferation and effector function during chronic antigenic stimulation. Furthermore, treatments that maintain redox balance promote T cell self-renewal and enhance anti-tumor immunity.
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