In vivo CRISPR screens reveal a HIF-1α-mTOR-network regulates T follicular helper versus Th1 cells.
Animals
Antibody Formation
Cell Differentiation
/ immunology
Clustered Regularly Interspaced Short Palindromic Repeats
Gene Expression
Gene Knockout Techniques
Germinal Center
/ immunology
Glycolysis
Hypoxia-Inducible Factor 1, alpha Subunit
/ genetics
Immunity, Humoral
/ immunology
Mechanistic Target of Rapamycin Complex 1
/ metabolism
Mice
T-Lymphocytes, Helper-Inducer
/ immunology
TOR Serine-Threonine Kinases
/ genetics
Th1 Cells
/ immunology
Virus Diseases
/ immunology
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
10 02 2022
10 02 2022
Historique:
received:
15
07
2021
accepted:
20
01
2022
entrez:
11
2
2022
pubmed:
12
2
2022
medline:
4
3
2022
Statut:
epublish
Résumé
T follicular helper (Tfh) cells provide signals to initiate and maintain the germinal center (GC) reaction and are crucial for the generation of robust, long-lived antibody responses, but how the GC microenvironment affects Tfh cells is not well understood. Here we develop an in vivo T cell-intrinsic CRISPR-knockout screen to evaluate Tfh and Th1 cells in an acute viral infection model to identify regulators of Tfh cells in their physiological setting. Using a screen of druggable-targets, alongside genetic, transcriptomic and cellular analyses, we identify a function of HIF-1α in suppressing mTORC1-mediated and Myc-related pathways, and provide evidence that VHL-mediated degradation of HIF-1α is required for Tfh development; an expanded in vivo CRISPR screen reveals multiple components of these pathways that regulate Tfh versus Th1 cells, including signaling molecules, cell-cycle regulators, nutrient transporters, metabolic enzymes and autophagy mediators. Collectively, our data serve as a resource for studying Tfh versus Th1 decisions, and implicate the VHL-HIF-1α axis in fine-tuning Tfh generation.
Identifiants
pubmed: 35145086
doi: 10.1038/s41467-022-28378-6
pii: 10.1038/s41467-022-28378-6
pmc: PMC8831505
doi:
Substances chimiques
Hif1a protein, mouse
0
Hypoxia-Inducible Factor 1, alpha Subunit
0
mTOR protein, mouse
EC 2.7.1.1
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
805Informations de copyright
© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
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