Cell
Volume 184, Issue 5, 4 March 2021, Pages 1245-1261.e21
Journal home page for Cell

Article
In vivo CRISPR screening reveals nutrient signaling processes underpinning CD8+ T cell fate decisions

https://doi.org/10.1016/j.cell.2021.02.021Get rights and content
Under an Elsevier user license
open archive

Highlights

  • Systematic discovery of metabolic regulators for CD8+ T cell fate decisions in vivo

  • Amino acids restrict quantity of T cell memory

  • Pofut1 loss promotes TEFF and TMEM responses by blocking terminal differentiation

  • Pofut1 links GDP-fucose availability to Notch-Rbpj signaling in fate decisions

Summary

How early events in effector T cell (TEFF) subsets tune memory T cell (TMEM) responses remains incompletely understood. Here, we systematically investigated metabolic factors in fate determination of TEFF and TMEM cells using in vivo pooled CRISPR screening, focusing on negative regulators of TMEM responses. We found that amino acid transporters Slc7a1 and Slc38a2 dampened the magnitude of TMEM differentiation, in part through modulating mTORC1 signaling. By integrating genetic and systems approaches, we identified cellular and metabolic heterogeneity among TEFF cells, with terminal effector differentiation associated with establishment of metabolic quiescence and exit from the cell cycle. Importantly, Pofut1 (protein-O-fucosyltransferase-1) linked GDP-fucose availability to downstream Notch-Rbpj signaling, and perturbation of this nutrient signaling axis blocked terminal effector differentiation but drove context-dependent TEFF proliferation and TMEM development. Our study establishes that nutrient uptake and signaling are key determinants of T cell fate and shape the quantity and quality of TMEM responses.

Keywords

T cell memory
metabolic heterogeneity
in vivo pooled CRISPR screening
terminal effector cell
immunometabolism
Notch
GDP-fucose
nutrient signaling
cell cycle exit
systems immunology

Cited by (0)

4

These authors contributed equally

5

Lead contact