Regulatory T cells (T reg cells), a distinct subset of CD4 + T cells, are necessary for the maintenance of immune self-tolerance and homeostasis 1,2 . Recent studies have demonstrated that T reg cells exhibit a unique metabolic profile, characterized by an increase in mitochondrial metabolism relative to other CD4 + effector subsets 3,4 . Furthermore, the T reg cell lineage-defining transcription factor, Foxp3, has been shown to promote respiration 5,6 ; however, it remains unknown whether the mitochondrial respiratory chain is required for the T cell-suppression capacity, stability and survival of T reg cells. Here we report that T reg cell-specific ablation of mitochondrial respiratory chain complex III in mice results in the development of fatal inflammatory disease early in life, without affecting T reg cell number. Mice that lack mitochondrial complex III specifically in T reg cells displayed a loss of T cell-suppression capacity without altering T reg cell proliferation and survival. T reg cells deficient in complex III showed decreased expression of genes associated with T reg function, whereas Foxp3 expression remained stable. Loss of complex III in T reg cells increased DNA methylation as well as the metabolites 2-hydroxyglutarate (2-HG) and succinate that inhibit the ten-eleven translocation (TET) family of DNA demethylases 7 . Thus, T reg cells require mitochondrial complex III to maintain immune regulatory gene expression and suppressive function.
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