The mammalian Target of Rapamycin (mTOR) regulates T helper cell differentiation through the selective activation of mTORC1 and mTORC2 signaling

mTOR has emerged as an important regulator of T helper cell differentiation. Here we demonstrate that T(H)1 and T(H)17 differentiation is selectively regulated by Rheb-dependent mTOR complex 1 (mTORC1) signaling. Rheb-deficient T cells fail to generate T(H)1 and T(H)17 responses in vitro and in vivo and cannot induce classical experimental autoimmune encephalomyelitis (EAE). However, they retain their ability to become T(H)2 cells. Alternatively, when mTORC2 signaling is deleted in T cells, they fail to generate T(H)2 cells in vitro and in vivo but preserve their ability to become T(H)1 and T(H)17 cells. Our data provide mechanisms by which the two distinct signaling pathways downstream of mTOR differentially regulate helper cell fate. These findings define a novel paradigm linking T cell differentiation with selective metabolic signaling pathways.