Fine-tuning of CD8 T cell mitochondrial respiration by MCJ/DnaJC15 dictates protection to influenza virus

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.