Metabolic signaling directs the reciprocal lineage decisions of αß and γδ T cells.
Sci Immunol
; 3(25)2018 07 06.
Article
em En
| MEDLINE
| ID: mdl-29980617
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 αß 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 αß 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 αß 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 αß and γδ T cell development and provide insight into metabolic control of cell signaling and fate decisions.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Diferenciação Celular
/
Subpopulações de Linfócitos T
/
Alvo Mecanístico do Complexo 1 de Rapamicina
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Sci Immunol
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos