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

Hongling Huang, Peipei Zhou, Jun Wei, Lingyun Long, Hao Shi, Yogesh Dhungana, Nicole M. Chapman, Guotong Fu, Jordy Saravia, Jana L. Raynor, Shaofeng Liu, Gustavo Palacios, Yong Dong Wang, Chenxi Qian, Jiyang Yu, Hongbo Chi

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


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. Metabolic changes associated with amino acid transport and nutrient signaling regulate the fate of effector T cell populations and the generation of memory T cell responses.

Original languageEnglish
Pages (from-to)1245-1261.e21
Issue number5
StatePublished - 4 Mar 2021
Externally publishedYes


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


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