Regulatory T cells require the phosphatase PTEN to restrain type 1 and follicular helper T-cell responses

The interplay between effector and regulatory T (Treg) cells is crucial for adaptive immunity, but how Treg control effector cell flexibility is elusive. We found that the phosphatase PTEN links Treg stability to the repression of TH1 and TFH (follicular helper) responses. Depletion of PTEN in Treg resulted in excessive TFH and germinal center responses and spontaneous inflammatory disease. These defects are considerably blocked by deletion of Interferon-γ, indicating coordinated control of TH1 and TFH responses. Mechanistically, PTEN maintains Treg stability and proper metabolic balance between glycolysis and mitochondrial fitness. Moreover, PTEN deficiency markedly upregulates mTORC2-Akt activity, and loss of this activity restores PTEN-deficient Treg function. Our studies establish a PTEN-mTORC2 axis that actively maintains Treg stability and coordinates Treg-mediated control of effector cell flexibility. We used microarrays to explore the gene expression profiles differentially expressed in CD4+CD25+Foxp3-YFP+ Treg cells from wild-type (WT; C57BL/6 crossed with Foxp3-Cre) and Ptenfl/flFoxp3-Cre (Ptenfl/fl mice crossed with Foxp3-Cre) mice