1. Metabolic signaling directs the reciprocal lineage decisions of αβ and γδ T cells.
- Author
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Yang, Kai, Blanco, Daniel Bastardo, Chen, Xiang, Dash, Pradyot, Neale, Geoffrey, Rosencrance, Celeste, Easton, John, Chen, Wenan, Cheng, Changde, Dhungana, Yogesh, KC, Anil, Awad, Walid, Guo, Xi-Zhi J., Thomas, Paul G., and Chi, Hongbo
- Subjects
RAPAMYCIN ,THYMOCYTES ,GLYCOLYSIS ,PHOSPHORYLATION ,HOMEOSTASIS ,T cells ,CELL communication ,METABOLIC regulation - Abstract
The interaction between extrinsic factors and intrinsic signal strength governs thymocyte development, but the mechanisms linking them remain elusive. We report that mechanistic target of rapamycin complex 1 (mTORC1) couples microenvironmental cues with metabolic programs to orchestrate the reciprocal development of two fundamentally distinct T cell lineages, the αβ and γδ T cells. Developing thymocytes dynamically engage metabolic programs including glycolysis and oxidative phosphorylation, as well as mTORC1 signaling. Loss of RAPTOR-mediated mTORC1 activity impairs the development of αβ T cells but promotes γδ T cell generation, associated with disrupted metabolic remodeling of oxidative and glycolytic metabolism. Mechanistically, we identify mTORC1-dependent control of reactive oxygen species production as a key metabolic signal in mediating αβ and γδ T cell development, and perturbation of redox homeostasis impinges upon thymocyte fate decisions and mTORC1-associated phenotypes. Furthermore, single-cell RNA sequencing and genetic dissection reveal that mTORC1 links developmental signals from T cell receptors and NOTCH to coordinate metabolic activity and signal strength. Our results establish mTORC1-driven metabolic signaling as a decisive factor for reciprocal and αβ T γδ cell development and provide insight into metabolic control of cell signaling and fate decisions. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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