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Cited by 67T-cell and B-cell ImmunologyPsoriasis: Treatment and PathogenesisIL-33, ST2, and ILC Pathways

IRF8‐dependent Molecular Complexes Control the Th9 Transcriptional Program

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Humblin, Etienne, Thibaudin, Marion, Chalmin, Fanny, Derangère, Valentin, Limagne, Emeric, Richard, Corentin, Flavell, Richard A., Chevrier, Sandy +6 more·2017·Nature Communications
DOI 10.1038/s41467-017-01070-wPMC PMC5727025
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Abstract

Interferon regulatory factors (IRF) have critical functions in lymphoid development and in immune response regulation. Although many studies have described the function of IRF4 in CD4 + T cells, few have focused on the IRF4 homologue, IRF8. Here, we show that IRF8 is required for Th9 differentiation in vitro and in vivo. IRF8 functions through a transcription factor complex consisting of IRF8, IRF4, PU.1 and BATF, which binds to DNA and boosts Il9 transcription. By contrast, IRF8 deficiency promotes the expression of other genes such as Il4 , as IRF8 dimerises with the transcriptional repressor ETV6 and inhibits Il4 expression. In vivo, IRF8 is essential for the anti-tumour effects of Th9 cells in mouse melanoma models. Our results show that IRF8 complexes boost the Th9 program and repress Il4 expression to modulate Th9 cell differentiation, thereby implicating IRF8 as a potential therapeutic target to affect Th9 responses in cancer therapy.

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  • PU.1 functions as a pioneer transcriptional factor that establishes enhancer accessibility in myeloid lineage cells and directly induces expression of other transcriptional factors, such as IRF8 and MEF2C.

    “Especially, PU.1 functions as a pioneer transcriptional factor that establishes enhancer accessibility in myeloid lineage cells and directly induces expression of other transcriptional factors (e.g., IRF8, MEF2C) [29, 64, 69, 70].”

    From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [70]

    The Introduction and Discussion identify PU.1 as a transcription factor and report that it partners with IRF8 in myeloid cells. They do not say that PU.1 acts as a pioneer factor, establishes enhancer accessibility, or directly induces IRF8 or MEF2C expression. The paper instead focuses on PU.1-containing complexes that regulate Th9 cytokine transcription; page numbers were not available in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • PU.1 binds ETS motifs and cooperates with IRF family members at composite IRF-ETS elements to regulate microglial immune programs, including phagocytic activity, cytokine production, TLR signaling, and complement activation.

    “Mechanistically, PU.1 binds ETS motifs and cooperates with IRF family members at composite IRF‐ETS elements to regulate microglial immune programs (phagocytic activity, cytokine production, TLR signaling, and complement activation) [39, 70, 71].”

    From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [70]

    The Discussion (page unavailable) says that IRF8 can partner with the ETS-family factor PU.1 at composite ETS–IRF sequences to activate transcription. The paper studies Th9-cell cytokine transcription, however; it does not establish that this partnership regulates microglial phagocytosis, cytokine production, TLR signaling, or complement activation. (LLM, conf=0.88)

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Authors
Humblin, E., Thibaudin, M., Chalmin, F., Derangère, V., Limagne, E., Richard, C., Flavell, R. A., Chevrier, S., Ladoire, S., Berger, H., Boidot, R., Apetoh, L., Végran, F., & Ghiringhelli, F.
Affiliations
  • Inserm (FR)
  • Centre Georges François Leclerc (FR)
  • Howard Hughes Medical Institute (US)
Corresponding author
  • Végran, Frédérique
  • Ghiringhelli, François
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-12-12
Volume
8
Issue
1
Pages
2085-2085
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-017-01070-w
PMC
PMC5727025
OpenAlex
W2774476207
Cited by
67
References
10
Citations by year
2026: 7 · 2025: 7 · 2024: 9 · 2023: 5 · 2022: 7 · 2021: 7 · 2020: 9 · 2019: 8 · 2018: 8
FWCI
3.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • European Commission (303719)
  • Agence Nationale de la Recherche (ANR-13-JSV3-0001, ANR-11-LABX-0021)
  • Institut National de la Santé et de la Recherche Médicale
  • Fondation ARC pour la Recherche sur le Cancer
  • Institut National Du Cancer
  • National Institutes of Health (UL1TR001863)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
  • Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
Keywords
IRF8, Th9 cells, IRF4, PU.1, BATF, transcription factor complex, ETV6, transcriptional repression, melanoma, antitumor immunity, CD4+ T cells, transcriptional repressor
MeSH terms
Interferon Regulatory Factor-8, Interferon Regulatory Factor-4, Proto-Oncogene Protein Spi-1, Animals, Cell Differentiation, Female, T-Lymphocytes, Helper-Inducer, Humans, Melanoma, Mice, Inbred C57BL, Proto-Oncogene Proteins, Transcription, Genetic, Trans-Activators, Interleukin-9, Xenograft Model Antitumor Assays, RNA, Small Interfering, Interferon Regulatory Factors, Basic-Leucine Zipper Transcription Factors, Mice, Gene Knockdown Techniques

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