STAT1 Controls the Functionality of Influenza-Primed CD4 T Cells but Therapeutic STAT4 Engagement Maximizes Their Antiviral Impact.
Mice
Animals
Humans
CD4-Positive T-Lymphocytes
Antiviral Agents
/ metabolism
Influenza, Human
T-Box Domain Proteins
/ metabolism
Interferon-gamma
/ metabolism
Transcription Factors
/ metabolism
Th1 Cells
STAT4 Transcription Factor
/ metabolism
Cell Differentiation
STAT1 Transcription Factor
/ metabolism
Journal
Journal of immunology (Baltimore, Md. : 1950)
ISSN: 1550-6606
Titre abrégé: J Immunol
Pays: United States
ID NLM: 2985117R
Informations de publication
Date de publication:
01 05 2023
01 05 2023
Historique:
received:
07
06
2022
accepted:
22
02
2023
pmc-release:
01
05
2024
medline:
19
4
2023
pubmed:
25
3
2023
entrez:
24
3
2023
Statut:
ppublish
Résumé
It is generally accepted that influenza A virus (IAV) infection promotes a Th1-like CD4 T cell response and that this effector program underlies its protective impact. Canonical Th1 polarization requires cytokine-mediated activation of the transcription factors STAT1 and STAT4 that synergize to maximize the induction of the "master regulator" Th1 transcription factor, T-bet. Here, we determine the individual requirements for these transcription factors in directing the Th1 imprint primed by influenza infection in mice by tracking virus-specific wild-type or T-bet-deficient CD4 T cells in which STAT1 or STAT4 is knocked out. We find that STAT1 is required to protect influenza-primed CD4 T cells from NK cell-mediated deletion and for their expression of hallmark Th1 attributes. STAT1 is also required to prevent type I IFN signals from inhibiting the induction of the Th17 master regulator, Rorγt, in Th17-prone T-bet-/- cells responding to IAV. In contrast, STAT4 expression does not appreciably impact the phenotypic or functional attributes of wild-type or T-bet-/- CD4 T cell responses. However, cytokine-mediated STAT4 activation in virus-specific CD4 T cells enhances their Th1 identity in a T-bet-dependent manner, indicating that influenza infection does not promote maximal Th1 induction. Finally, we show that the T-bet-dependent protective capacity of CD4 T cell effectors against IAV is optimized by engaging both STAT1 and STAT4 during Th1 priming, with important implications for vaccine strategies aiming to generate T cell immunity.
Identifiants
pubmed: 36961447
pii: 263555
doi: 10.4049/jimmunol.2200407
pmc: PMC10121883
mid: NIHMS1878206
doi:
Substances chimiques
Antiviral Agents
0
T-Box Domain Proteins
0
Interferon-gamma
82115-62-6
Transcription Factors
0
STAT4 Transcription Factor
0
Stat1 protein, mouse
0
STAT1 Transcription Factor
0
Stat4 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1292-1304Subventions
Organisme : NIAID NIH HHS
ID : R01 AI167994
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI146647
Pays : United States
Informations de copyright
Copyright © 2023 by The American Association of Immunologists, Inc.
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