Abstract
Abstract The thymus supports and guides the generation of a diverse repertoire of mature T cells from precursors derived from the bone marrow. The interaction between extrinsic factors and intrinsic signal strength governs thymocyte development, but the mechanisms linking these two aspects of T cell development remain elusive. Capitalizing on genetic deletion of RAPTOR, here we report that RAPTOR-dependent mTORC1 signaling couples microenvironmental cues with metabolic programs in orchestrating reciprocal development of two fundamentally distinct T cell lineages: αβ and γδ T cells. Loss of RAPTOR impairs αβ but promotes γδ T cell development while disrupting metabolic remodeling of oxidative and glycolytic metabolism. Mechanistically, we identify mTORC1-dependent control of reactive oxygen species (ROS) production as a key metabolic signal that, upon perturbation of redox homeostasis, impinges upon T cell fate decision. Our results establish mTORC1-driven metabolic signaling as a fundamental mechanism underlying thymocyte lineage choices.
Published Version
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