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

Regulatory T cells (T.sub.reg cells), a distinct subset of CD4.sup.+ T cells, are necessary for the maintenance of immune self-tolerance and homeostasis.sup.1,2. Recent studies have demonstrated that T.sub.reg cells exhibit a unique metabolic profile, characterized by an increase in mitochondrial metabolism relative to other CD4.sup.+ effector subsets.sup.3,4. Furthermore, the T.sub.reg cell lineage-defining transcription factor, Foxp3, has been shown to promote respiration.sup.5,6; however, it remains unknown whether the mitochondrial respiratory chain is required for the T cell-suppression capacity, stability and survival of T.sub.reg cells. Here we report that T.sub.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.sub.reg cell number. Mice that lack mitochondrial complex III specifically in T.sub.reg cells displayed a loss of T cell-suppression capacity without altering T.sub.reg cell proliferation and survival. T.sub.reg cells deficient in complex III showed decreased expression of genes associated with T.sub.reg function, whereas Foxp3 expression remained stable. Loss of complex III in T.sub.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.sup.7. Thus, T.sub.reg cells require mitochondrial complex III to maintain immune regulatory gene expression and suppressive function.Specific ablation of mitochondrial complex III subunits in T.sub.reg cells in mice results in inflammatory disease, altered T.sub.reg gene expression and defective T.sub.reg function, indicating a key functional role for mitochondrial complex III in T.sub.reg cells.
Author(s): Samuel E. Weinberg [sup.1] , Benjamin D. Singer [sup.1] [sup.2] , Elizabeth M. Steinert [sup.1] , Carlos A. Martinez [sup.2] , Manan M. Mehta [sup.1] , Inmaculada Martínez-Reyes [sup.1] [...]