AKT hyperactivation confers a Th1 phenotype in thymic Treg cells deficient in TGF‐β receptor II signaling

The generation of CD 4 + F oxp3 + T reg cells in the thymus is crucial for immune homeostasis and self‐tolerance. Recent studies have shown T reg‐cell plasticity when T h‐related transcriptional factors and cytokines are present. However, the mechanisms that maintain the stability of T reg cells are poorly understood. Here, using mice with a T ‐cell‐specific deletion of the transforming growth factor‐β receptor 2 ( T gfbr2 −/− mice), we identify the restriction of AKT activation as a key event for the control of T reg‐cell stability in T h1 inflammation. AKT regulation was evident in thymic CD 4 + F oxp3 + T reg cells before they egressed to peripheral tissues. CD 4 + F oxp3 + thymocytes from mice with the T gfbr2 deletion expressed high levels of CXCR 3 and T ‐bet, and produced IFN ‐γ and TNF ‐α. Thymic T gfbr2 −/− T reg cells also showed an increase in the activation of AKT pathway. Enhanced AKT activity induced the expression of IFN ‐γ both in natural and inducible T reg cells. Inhibition of AKT activity markedly attenuated the expression of IFN ‐γ and TNF ‐α in thymic T gfbr2 −/− T reg cells in vivo. In addition, mixed bone marrow transplantation showed that TGF ‐β signaling maintained T reg‐cell stability in an intrinsic manner. Our results demonstrate that AKT hyperactivation contributes to the conversion of T reg cells to a T h1 phenotype.