Metabolic signaling directs the reciprocal lineage decisions of alphabeta and gammadelta T cells

Science immunology
Published

July 6, 2018

Doi

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 alphabeta and gammadelta 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 alphabeta T cells but promotes gammadelta 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 alphabeta and gammadelta 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 alphabeta and gammadelta T cell development and provide insight into metabolic control of cell signaling and fate decisions.