Functional Reprogramming of Regulatory T cells in the absence of Foxp3

Regulatory T cells (T(reg) cells) deficient in the transcription factor Foxp3 lack suppressor function and manifest a T effector (T(eff)) cell-like phenotype. We demonstrate that Foxp3 deficiency dysregulates metabolic checkpoint kinase mTORC2 signaling and gives rise to augmented aerobic glycolysis and oxidative phosphorylation. Specific deletion of the mTORC2 adaptor gene Rictor in Foxp3-deficient T(reg) cells ameliorated disease in a Foxo1 transcription factor-dependent manner. Rictor deficiency reestablished a subset of T(reg) cell genetic circuits and suppressed the T(eff) cell-like glycolytic and respiratory programs, which contributed to immune dysregulation. Treatment of T(reg) cells from patients with FOXP3 deficiency with mTOR inhibitors similarly antagonized their T(eff) cell-like program and restored suppressive function. Thus, regulatory function can be reestablished in Foxp3-deficient T(reg) cells by targeting their metabolic pathways, providing opportunities to restore tolerance in T(reg) cell disorders.