Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses
Open accessAbstract
In the course of infection or autoimmunity, particular transcription factors orchestrate the differentiation of T(H)1, T(H)2 or T(H)17 effector cells, the responses of which are limited by a distinct lineage of suppressive regulatory T cells (T(reg)). T(reg) cell differentiation and function are guided by the transcription factor Foxp3, and their deficiency due to mutations in Foxp3 results in aggressive fatal autoimmune disease associated with sharply augmented T(H)1 and T(H)2 cytokine production. Recent studies suggested that Foxp3 regulates the bulk of the Foxp3-dependent transcriptional program indirectly through a set of transcriptional regulators serving as direct Foxp3 targets. Here we show that in mouse T(reg) cells, high amounts of interferon regulatory factor-4 (IRF4), a transcription factor essential for T(H)2 effector cell differentiation, is dependent on Foxp3 expression. We proposed that IRF4 expression endows T(reg) cells with the ability to suppress T(H)2 responses. Indeed, ablation of a conditional Irf4 allele in T(reg) cells resulted in selective dysregulation of T(H)2 responses, IL4-dependent immunoglobulin isotype production, and tissue lesions with pronounced plasma cell infiltration, in contrast to the mononuclear-cell-dominated pathology typical of mice lacking T(reg) cells. Our results indicate that T(reg) cells use components of the transcriptional machinery, promoting a particular type of effector CD4(+) T cell differentiation, to efficiently restrain the corresponding type of the immune response.
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An increasing list of transcription factors, including IRF4, STAT3, T-bet, GATA3, Bcl-6, and Blimp-1, regulate both effector T cell function and regulatory T cell function.
“an increasing list of transcription factors now shown to regulate both effector T cell function and regulatory T cell function, including IRF4, STAT3, T-bet, GATA3, Bcl-6, and Blimp-1 [98–105].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [98]
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- Authors
- Zheng, Y., Chaudhry, A., Kas, A., deRoos, P., Kim, J. M., Chu, T.-T., Corcoran, L., Treuting, P., Klein, U., & Rudensky, A. Y.
- Affiliations
- Howard Hughes Medical Institute (US)
- Walter and Eliza Hall Institute of Medical Research (AU)
- University of Washington (US)
- Herbert Irving Comprehensive Cancer Center (US)
- Corresponding author
- Rudensky, Alexander Y.
- ORCID
- Venue
- Nature
- Published
- 2009-02-01
- Volume
- 458
- Issue
- 7236
- Pages
- 351-356
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2864791
- OpenAlex
- W2080935386
- Cited by
- 958
- References
- 31
- Citations by year
- 2026: 23 · 2025: 28 · 2024: 41 · 2023: 35 · 2022: 47 · 2021: 50 · 2020: 56 · 2019: 58 · 2018: 54 · 2017: 59 · 2016: 51 · 2015: 74 · 2014: 76 · 2013: 74 · 2012: 73
- FWCI
- 33.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- regulatory T cells, IRF4, Foxp3, Th2 immune response, Treg differentiation, transcriptional regulation, autoimmune disease, IL-4, immunoglobulin isotype switching, plasma cell infiltration, CD4+ T cell differentiation, suppressor function
- MeSH terms
- Interferon Regulatory Factor-4, Animals, Autoimmune Diseases, Cell Differentiation, Immunoglobulin E, Immunoglobulin G, Lymphocyte Activation, Mice, Inbred C57BL, Thymus Gland, Th2 Cells, CD4 Lymphocyte Count, T-Lymphocytes, Regulatory, Interferon Regulatory Factors, Mice, Forkhead Transcription Factors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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