Mitochondrial complex III is essential for regulatory T cell suppressive function

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 T(reg) cell suppressive capacity, stability, and survival. Here we report that T(reg) cell-specific ablation of mitochondrial respiratory chain complex III results in the development of a fatal inflammatory disease early in life, without impacting T(reg) cell number. Mice lacking mitochondrial complex III specifically in T(reg) cells displayed a loss of T(reg) cell suppressive capacity without altering T(reg) cell proliferation and survival. T(reg) cells deficient in complex III had decreased expression of genes associated with T(reg) function while maintaining stable Foxp3 expression. 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.