Unraveling Molecular Mechanisms Underlying the Development of Unconventional T Cells

The thymus supports and guides the generation of a diverse repertoire of mature T cells from precursors derived from the bone marrow. In addition to conventional CD4 and CD8 T cells, innate-like T cells also develop in the thymus and share features of the adaptive and the innate immune system. These ‘unconventional’ T cells have emerging roles in tissue homeostasis and disease, but the molecular mechanisms underpinning their development remain elusive. In this study, we uncovered the roles of the molecules RAPTOR and PTEN in the thymic development of unconventional T cells. Capitalizing on genetic deletion of RAPTOR, we found RAPTOR-dependent mTORC1 signaling couples microenvironmental cues with metabolic programs to orchestrate the reciprocal development of two fundamentally distinct T cell lineages: αβ and γδ-T cells. Loss of RAPTOR impaired αβ but promoted γδ-T cell development while disrupting metabolic remodeling of oxidative and glycolytic metabolism. Mechanistically, we identified 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 decisions. Additionally, we showed that PTEN acts as a cell-intrinsic molecular brake for the thymic development of unconventional T cells. Our results establish mTORC1-driven metabolic signaling as a fundamental mechanism underlying thymocyte lineage choices and uncover PTEN as a cell-intrinsic molecular brake in the development of unconventional T cells