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 an effector T (T_eff) cell-like phenotype. We demonstrate that Foxp3 deficiency dysregulates metabolic checkpoint kinase mammalian target of rapamycin (mTOR) complex 2 (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 re-established 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 re-established in Foxp3-deficient T_reg cells by targeting their metabolic pathways, providing opportunities to restore tolerance in T_reg cell disorders.