mTOR has emerged as an important regulator of T helper cell differentiation. Here we demonstrate that TH1 and TH17 differentiation is selectively regulated by Rheb-dependent mTOR complex 1 (mTORC1) signaling. Rheb-deficient T cells fail to generate TH1 and TH17 responses in vitro and in vivo and cannot induce classical experimental autoimmune encephalomyelitis (EAE). However, they retain their ability to become TH2 cells. Alternatively, when mTORC2 signaling is deleted in T cells, they fail to generate TH2 cells in vitro and in vivo but preserve their ability to become TH1 and TH17 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.

mTOR is an evolutionarily conserved serine/threonine kinase that plays a central role in integrating environmental cues in the form of growth factors, amino acids, and energy. In the study of the immune system, mTOR is emerging as a critical regulator of immune function because of its role in sensing and integrating cues from the immune microenvironment. With the greater appreciation of cellular metabolism as an important regulator of immune cell function, mTOR is proving to be a vital link between immune function and metabolism. In this review, we discuss the ability of mTOR to direct the adaptive immune response. Specifically, we focus on the role of mTOR in promoting differentiation, activation, and function in T cells, B cells, and antigen-presenting cells.

Tuberous sclerosis (TSC) is a hamartoma syndrome caused by mutations in