Mitochondrial complex III is essential for suppressive function of regulatory T cells.

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.