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 demethylases⁷. Thus, T_reg cells require mitochondrial complex III to maintain immune regulatory gene expression and suppressive function.