美国纪念斯隆-凯特琳癌症中心Craig B. Thompson研究小发现，线粒体氧化磷酸化的受损能够限制被长期抗原刺激下T细胞的自我更新。该项研究成果于2020年7月13日在线发表在《自然—免疫学》杂志上。

Title: Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen

Author: 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

Issue&Volume: 2020-07-13

Abstract: 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. Thompson and colleagues show that repetitive antigenic stimulation within the tumor environment triggers mitochondrial dysfunction by inhibiting oxidative phosphorylation, which leads to T cell exhaustion.

DOI: 10.1038/s41590-020-0725-2

Source: https://www.nature.com/articles/s41590-020-0725-2