Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses

The interplay between effector T cells and regulatory T cells (T-reg cells) is crucial for adaptive immunity, but how T-reg cells control diverse effector responses is elusive. We found that the phosphatase PTEN links T-reg cell stability to repression of type 1 helper T cell (T(H)1 cell) and follicular helper T cell (T-FH cell) responses. Depletion of PTEN in T-reg cells resulted in excessive T-FH cell and germinal center responses and spontaneous inflammatory disease. These defects were considerably blocked by deletion of interferon-gamma, indicating coordinated control of T(H)1 and T-FH responses. Mechanistically, PTEN maintained T-reg cell stability and metabolic balance between glycolysis and mitochondrial fitness. Moreover, PTEN deficiency upregulates activity of the metabolic checkpoint kinase complex mTORC2 and the serine-threonine kinase Akt, and loss of this activity restores functioning of PTEN-deficient T-reg cells. Our studies establish a PTEN-mTORC2 axis that maintains T-reg cell stability and coordinates T-reg cell-mediated control of effector responses.