mTORC1-dependent metabolic reprogramming orchestrates T cell activation and fate decisions (IRM10P.750)

Naive and activated T cells exhibit distinct bioenergetic and biosynthetic demands. Naive T cells are in a quiescent state and utilize a catabolic metabolism, whereas antigen-stimulated T cells are highly anabolic. How the metabolic reprogramming is regulated by immune signaling is unclear. In the present study, we reveal that Raptor/mTORC1 orchestrates antigen-induced metabolic reprogramming, and this is a key process to mediate T cell exit from quiescence for ensuing activation and differentiation. Raptor is essential for the integration of T cell receptor and CD28 co-stimulatory signals for sustained mTORC1 activation. Ablation of Raptor in T cells impaired T cell exit from quiescence, indicated by defective cell growth and cell cycle entry. Raptor deficiency abrogated multiple metabolic programs, including glycolysis, lipid synthesis and oxidative phosphorylation, which are required for antigen-triggered exit from quiescence. Aside from the requirement of Raptor in T cell exit from quiescence, Raptor/mTORC1 linked glucose metabolism to the initiation of Th2 cell differentiation through regulating cytokine receptor expression and cytokine responsiveness. Raptor/mTORC1 also impinged upon the differentiation of other T cell lineages including Th1 and Th17 cells. Our studies indicate that Raptor/mTORC1-dependent metabolic reprogramming fuels quiescence exit of naive T cells, and this in turn coordinates lymphocyte expansion and differentiation in adaptive immune responses.