Bromodomain protein BRD4 directs and sustains CD8 T cell differentiation during infection.
Animals
CD8-Positive T-Lymphocytes
/ cytology
Cell Differentiation
/ immunology
Chromatin
/ metabolism
Enhancer Elements, Genetic
/ genetics
Mice, Knockout
Neoplasms
/ immunology
Nuclear Proteins
/ deficiency
Protein Binding
RNA Interference
Transcription Factors
/ deficiency
Transcription, Genetic
Virus Diseases
/ immunology
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
02 08 2021
02 08 2021
Historique:
received:
24
11
2020
revised:
10
03
2021
accepted:
03
05
2021
entrez:
26
5
2021
pubmed:
27
5
2021
medline:
3
11
2021
Statut:
ppublish
Résumé
In response to infection, pathogen-specific CD8 T cells differentiate into functionally diverse effector and memory T cell populations critical for resolving disease and providing durable immunity. Through small-molecule inhibition, RNAi studies, and induced genetic deletion, we reveal an essential role for the chromatin modifier and BET family member BRD4 in supporting the differentiation and maintenance of terminally fated effector CD8 T cells during infection. BRD4 bound diverse regulatory regions critical to effector T cell differentiation and controlled transcriptional activity of terminal effector-specific super-enhancers in vivo. Consequentially, induced deletion of Brd4 or small molecule-mediated BET inhibition impaired maintenance of a terminal effector T cell phenotype. BRD4 was also required for terminal differentiation of CD8 T cells in the tumor microenvironment in murine models, which we show has implications for immunotherapies. Taken together, these data reveal an unappreciated requirement for BRD4 in coordinating activity of cis regulatory elements to control CD8 T cell fate and lineage stability.
Identifiants
pubmed: 34037670
pii: 212191
doi: 10.1084/jem.20202512
pmc: PMC8160575
pii:
doi:
Substances chimiques
Brd4 protein, mouse
0
Chromatin
0
Nuclear Proteins
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : R00 CA234430
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI124465
Pays : United States
Organisme : NCI NIH HHS
ID : K99 CA234430
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI109976
Pays : United States
Organisme : NCI NIH HHS
ID : K00 CA222711
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA239165
Pays : United States
Organisme : NIAID NIH HHS
ID : R37 AI067545
Pays : United States
Organisme : NIAID NIH HHS
ID : P01 AI132122
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI130152
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021 Milner et al.
Déclaration de conflit d'intérêts
A.W. Goldrath reported “other” from Pandion Therapeutics and “other” from ArsenalBio outside the submitted work, and is on the SAB of Pandion Therapeutics and ArsenalBio. J. Qi reported “other” from Epiphanes outside the submitted work. No other disclosures were reported.
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