T Cell Exit from Quiescence and Differentiation into Th2 Cells Depend on Raptor-mTORC1-Mediated Metabolic Reprogramming

• Published in: Immunity (Cambridge, Mass.) Vol. 39; no. 6; pp. 1043 - 1056
• Main Authors: Yang, Kai, Shrestha, Sharad, Zeng, Hu, Karmaus, Peer W.F., Neale, Geoffrey, Vogel, Peter, Guertin, David A., Lamb, Richard F., Chi, Hongbo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12-12-2013; Elsevier Limited
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Cell Cycle; Cell Differentiation; Cell Proliferation; Cells, Cultured; Cytokines - metabolism; Gene Deletion; Gene expression; Glucose; Glucose - metabolism; Lipids; Lymphocyte Activation - physiology; Lymphocytes; Mice; Mice, Inbred C57BL; Regulatory-Associated Protein of mTOR; Rodents; Signal Transduction; T cell receptors; T-Lymphocytes - cytology; T-Lymphocytes - immunology; Th2 Cells - cytology; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2013.09.015

Naive T cells respond to antigen stimulation by exiting from quiescence and initiating clonal expansion and functional differentiation, but the control mechanism is elusive. Here we describe that Raptor-mTORC1-dependent metabolic reprogramming is a central determinant of this transitional process. Loss of Raptor abrogated T cell priming and T helper 2 (Th2) cell differentiation, although Raptor function is less important for continuous proliferation of actively cycling cells. mTORC1 coordinated multiple metabolic programs in T cells including glycolysis, lipid synthesis, and oxidative phosphorylation to mediate antigen-triggered exit from quiescence. mTORC1 further linked glucose metabolism to the initiation of Th2 cell differentiation by orchestrating cytokine receptor expression and cytokine responsiveness. Activation of Raptor-mTORC1 integrated T cell receptor and CD28 costimulatory signals in antigen-stimulated T cells. Our studies identify a Raptor-mTORC1-dependent pathway linking signal-dependent metabolic reprogramming to quiescence exit, and this in turn coordinates lymphocyte activation and fate decisions in adaptive immunity.
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•mTORC1-dependent metabolic reprogramming drives exit of T cells from quiescence•mTORC1 coordinates T cell glycolysis, lipogenesis, and oxidative phosphorylation•Raptor links glucose metabolism to cytokine responsiveness and Th2 cell generation•Raptor integrates TCR and CD28 costimulation signals