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

• Published in: Immunity (Cambridge, Mass.) Mass.), 2016-06, Vol.44 (6), p.1299-1311
• Main Authors: Champagne, Devin P., Hatle, Ketki M., Fortner, Karen A., D’Alessandro, Angelo, Thornton, Tina M., Yang, Rui, Torralba, Daniel, Tomás-Cortázar, Julen, Jun, Yong Woong, Ahn, Kyo Han, Hansen, Kirk C., Haynes, Laura, Anguita, Juan, Rincon, Mercedes
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Animals; CD8-Positive T-Lymphocytes - physiology; Cell growth; Cell Respiration; Cells, Cultured; Cytokines; Electron Transport Chain Complex Proteins - metabolism; Experiments; Flow cytometry; Gene expression; Glucose; Immunologic Memory; Infections; Influenza; Influenza virus; Interferon-gamma - metabolism; Lymphocyte Activation; Lymphocytes; Metabolism; Metabolome; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy; Mitochondria - metabolism; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; Orthomyxoviridae - immunology; Orthomyxoviridae Infections - immunology; Ovarian cancer; Oxidative Phosphorylation; Proteins; Respiration; Viral infections
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2016.02.018

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-γ. 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. •MCJ is a novel negative regulator of mitochondrial respiration in CD8+ T cells•Increased mitochondrial ATP in MCJ-deficient CD8+ T cells enhances cytokine secretion•MCJ adapts effector CD8+ T cell metabolism during the contraction phase•MCJ-deficient memory CD8+ T cells confer superior protection against influenza virus The endogenous molecular mechanisms controlling mitochondrial respiration in CD8+ T cells are not fully understood. In this issue of Immunity, Rincon and colleagues reveal that MCJ is a negative regulator of mitochondrial respiration in CD8+ T cells. Loss of MCJ enhances protective activity of memory CD8+ T cells against influenza virus.