Fine-Tuning of CD8+ T Cell Mitochondrial Metabolism by the Respiratory Chain Repressor MCJ Dictates Protection to Influenza Virus

被引:55
作者
Champagne, Devin P. [1 ]
Hatle, Ketki M. [1 ]
Fortner, Karen A. [1 ]
D'Alessandro, Angelo [2 ]
Thornton, Tina M. [1 ]
Yang, Rui [1 ]
Torralba, Daniel [1 ]
Tomas-Cortazar, Julen [3 ]
Jun, Yong Woong [4 ]
Ahn, Kyo Han [4 ]
Hansen, Kirk C. [2 ]
Haynes, Laura [5 ,6 ]
Anguita, Juan [3 ,7 ]
Rincon, Mercedes [1 ]
机构
[1] Univ Vermont, Dept Med, Program Immunobiol, Burlington, VT 05405 USA
[2] Univ Colorado Denver, Dept Biochem & Mol Genet, Aurora, CO 80045 USA
[3] Ctr Cooperat Res Biosci CIC bioGUNE, Derio 48160, Bizkaia, Spain
[4] Pohang Univ Sci & Technol POSTECH, Ctr Electrophoto Behav Adv Mol Syst, Dept Chem, Pohang 790784, Gyeongbuk, South Korea
[5] Univ Connecticut, Ctr Hlth, Ctr Aging, Farmington, CT 06030 USA
[6] Univ Connecticut, Ctr Hlth, Dept Immunol, Farmington, CT 06030 USA
[7] Basque Fdn Sci, Ikerbasque, Bilbao, Bizkaia, Spain
关键词
GENE-EXPRESSION; MEMORY; METHYLATION; EFFECTOR; DIFFERENTIATION; MCJ/DNAJC15;
D O I
10.1016/j.immuni.2016.02.018
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Mitochondrial respiration is regulated in CD8(+) T cells during the transition from naive to effector and memory cells, but mechanisms controlling this process have not been defined. Here we show that MCJ (methylation-controlled J protein) acted as an endogenous break for mitochondrial respiration in CD8(+) T cells by interfering with the formation of electron transport chain respiratory supercomplexes. Metabolic profiling revealed enhanced mitochondrial metabolism in MCJ-deficient CD8(+) T cells. Increased oxidative phosphorylation and subcellular ATP accumulation caused by MCJ deficiency selectively increased the secretion, but not expression, of interferon-gamma. MCJ also adapted effector CD8(+) T cell metabolism during the contraction phase. Consequently, memory CD8(+) T cells lacking MCJ provided superior protection against influenza virus infection. Thus, MCJ offers a mechanism for fine-tuning CD8(+) T cell mitochondrial metabolism as an alternative to modulating mitochondrial mass, an energetically expensive process. MCJ could be a therapeutic target to enhance CD8(+) T cell responses.
引用
收藏
页码:1299 / 1311
页数:13
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