Akt and mTOR pathways differentially regulate the development of natural and inducible T(H)17 cells

Natural T helper 17 (nT(H)17) cells are a population of interleukin 17 (IL-17)-producing cells that acquire effector function in the thymus during development. Here we demonstrate that the serine/threonine kinase Akt plays a critical role in regulating nT(H)17 cell development. While Akt and the downstream mTORC1–ARNT–HIFα axis were required for inducible T(H)17 (iT(H)17) cell generation in the periphery, nT(H)17 cells developed independently of mTORC1. In contrast, mTORC2 and inhibition of Foxo proteins were critical for nT(H)17 cell development. Moreover, Akt controlled T(H)17 subsets through distinct isoforms, as deletion of Akt2, but not Akt1, led to defective iT(H)17 cell generation. These findings reveal novel mechanisms regulating nT(H)17 cell development and previously unknown roles of Akt and mTOR in shaping T cell subsets.