CRISPR screens unveil signal hubs for nutrient licensing of T cell immunity

Nature. 2021 Dec;600(7888):308-313. doi: 10.1038/s41586-021-04109-7. Epub 2021 Nov 18.

Abstract

Nutrients are emerging regulators of adaptive immunity1. Selective nutrients interplay with immunological signals to activate mechanistic target of rapamycin complex 1 (mTORC1), a key driver of cell metabolism2-4, but how these environmental signals are integrated for immune regulation remains unclear. Here we use genome-wide CRISPR screening combined with protein-protein interaction networks to identify regulatory modules that mediate immune receptor- and nutrient-dependent signalling to mTORC1 in mouse regulatory T (Treg) cells. SEC31A is identified to promote mTORC1 activation by interacting with the GATOR2 component SEC13 to protect it from SKP1-dependent proteasomal degradation. Accordingly, loss of SEC31A impairs T cell priming and Treg suppressive function in mice. In addition, the SWI/SNF complex restricts expression of the amino acid sensor CASTOR1, thereby enhancing mTORC1 activation. Moreover, we reveal that the CCDC101-associated SAGA complex is a potent inhibitor of mTORC1, which limits the expression of glucose and amino acid transporters and maintains T cell quiescence in vivo. Specific deletion of Ccdc101 in mouse Treg cells results in uncontrolled inflammation but improved antitumour immunity. Collectively, our results establish epigenetic and post-translational mechanisms that underpin how nutrient transporters, sensors and transducers interplay with immune signals for three-tiered regulation of mTORC1 activity and identify their pivotal roles in licensing T cell immunity and immune tolerance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CRISPR-Cas Systems* / genetics
  • Carrier Proteins / metabolism
  • Female
  • Forkhead Transcription Factors / metabolism
  • Gene Editing*
  • Genome / genetics
  • Homeostasis
  • Immune Tolerance
  • Inflammation / pathology
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Neoplasms / immunology
  • Nuclear Proteins / metabolism
  • Nutrients* / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Interaction Maps*
  • Proteolysis
  • S-Phase Kinase-Associated Proteins / metabolism
  • T-Lymphocytes, Regulatory* / immunology
  • T-Lymphocytes, Regulatory* / metabolism
  • Trans-Activators / metabolism

Substances

  • Carrier Proteins
  • castor1 protein, mouse
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Nuclear Proteins
  • Proteasome Endopeptidase Complex
  • S-Phase Kinase-Associated Proteins
  • SAGA complex, mouse
  • Sec13 protein, mouse
  • SEC31A protein, mouse
  • Trans-Activators
  • Sgf29 protein, mouse