Fine-Tuning of CD8(+) T Cell Mitochondrial Metabolism by the Respiratory Chain Repressor MCJ Dictates Protection to Influenza Virus.
Fine-Tuning of CD8(+) T Cell Mitochondrial Metabolism by the Respiratory Chain Repressor MCJ Dictates Protection to Influenza Virus.
复制标题
DOI：
10.1016/j.immuni.2016.02.018
复制
发表时间：
2016-06-21
期刊：
影响因子：
32.4
通讯作者：
Rincon M
中科院分区：
文献类型：
--
作者：
Champagne DP;Hatle KM;Fortner KA;D'Alessandro A;Thornton TM;Yang R;Torralba D;Tomás-Cortázar J;Jun YW;Ahn KH;Hansen KC;Haynes L;Anguita J;Rincon M
在 CD8 T 细胞从幼稚细胞向效应细胞和记忆细胞转变的过程中，线粒体呼吸受到严格调节，但控制这一过程的机制尚未明确。在这里，我们发现 MCJ/DnaJC15 通过干扰电子传递链 (ETC) 呼吸超复合物的形成，充当 CD8 T 细胞线粒体呼吸的内源性中断。代谢分析揭示了 MCJ 缺陷的 CD8 细胞中线粒体代谢增强。 MCJ 缺失导致氧化磷酸化和亚细胞 ATP 积累增加，选择性增加 IFNγ 的分泌，但不增加 IFNγ 的表达。 MCJ 还可以在收缩期调节效应 CD8 T 细胞的代谢。因此，缺乏 MCJ 的记忆 CD8 细胞在提供针对流感病毒感染的保护方面更胜一筹。因此，MCJ 提供了一种微调 CD8 细胞中线粒体代谢的新机制，作为调节线粒体质量的替代方案，而调节线粒体质量是一个能量昂贵的过程。 MCJ 可能是增强 CD8 细胞反应的新治疗靶点。
Mitochondrial respiration is tightly regulated in CD8 T cells during the transition from naïve to effector and memory cells, but the mechanisms that control this process have not been defined. Here we show that MCJ/DnaJC15 acts as an endogenous break for mitochondrial respiration in CD8 T cells by interfering with the formation of electron transport chain (ETC) respiratory supercomplexes. Metabolic profiling reveals an enhanced mitochondrial metabolism in MCJ-deficient CD8 cells. Increased oxidative phosphorylation and subcellular ATP accumulation caused by the loss of MCJ selectively increase the secretion, but not the expression, of IFNγ. MCJ also serves to adapt effector CD8 T cell metabolism during the contraction phase. Consequently, memory CD8 cells lacking MCJ are superior in providing protection against influenza virus infection. Thus, MCJ offers a novel mechanism for fine-tuning mitochondrial metabolism in CD8 cells, as an alternative to modulating mitochondrial mass, which is an energetically expensive process. MCJ could be a new therapeutic target to enhance CD8 cell responses.