Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells
Open accessAbstract
Interferon-regulatory factor 4 (IRF4) is essential for the development of T helper 2 (Th2) and Th17 cells. Herein, we report that IRF4 is also crucial for the development and function of an interleukin-9 (IL-9)-producing CD4(+) T cell subset designated Th9. IRF4-deficient CD4(+) T cells failed to develop into IL-9-producing Th9 cells, and IRF4-specific siRNA inhibited IL-9 production in wild-type CD4(+) T cells. Chromatin-immunoprecipitation (ChIP) analyses revealed direct IRF4 binding to the Il9 promoter in Th9 cells. In a Th9-dependent asthma model, neutralization of IL-9 substantially ameliorated asthma symptoms. The relevance of these findings is emphasized by the fact that the induction of IL-9 production also occurs in human CD4(+) T cells accompanied by the upregulation of IRF4. Our data clearly demonstrate the central function of IRF4 in the development of Th9 cells and underline the contribution of this T helper cell subset to the pathogenesis of asthma.
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In Th9 cells, IL-9 gene expression is regulated by TGFβ, IL-4, and IL-33 and transcription factors like PU.1, STAT6, GATA3, and IRF4.
“In these cells, IL-9 gene expression is regulated by the cytokines TGFβ, IL-4, and IL-33 and transcription factors like PU.1, STAT6, GATA3, and IRF4.19–22”
From PU.1-driven Th9 Cells Promote Colorectal Cancer in Experimental Colitis Models Through Il-6 Effects in Intestinal Epithelial Cells (2022) · cites this paper as [20]
PU.1, rather than IRF4, GATA3, or STAT6, is the main driver for Th9 cell differentiation.
“Moreover, the transcription factor PU.1, rather than IRF4, GATA3, or STAT6, is the main driver for Th9 cell differentiation.20, 21”
From PU.1-driven Th9 Cells Promote Colorectal Cancer in Experimental Colitis Models Through Il-6 Effects in Intestinal Epithelial Cells (2022) · cites this paper as [20]
Cites
Ivanov, I. I., McKenzie, B. S., Zhou, L., Tadokoro, C. E., Lepelley, A., Lafaille, J. J., Cua, D. J., & Littman, D. R. (2006) · Cell · doi:10.1016/j.cell.2006.07.035 · Cited by 5,145 · see citing works
Zheng, W.-P., & Flavell, R. A. (1997) · Cell · doi:10.1016/s0092-8674(00)80240-8 · Cited by 2,384 · see citing works
Dardalhon, V., Awasthi, A., Kwon, H., Galileos, G., Gao, W., Sobel, R. A., Mitsdoerffer, M., Strom, T. B., Elyaman, W., Ho, I.-C., et al. (2008) · Nature Immunology · doi:10.1038/ni.1677 · Cited by 1,122 · see citing works
Requirement for the Transcription Factor LSIRF/IRF4 for Mature B and T Lymphocyte Function
Mittrücker, H.-W., Matsuyama, T., Grossman, A., Kündig, T. M., Potter, J., Shahinian, A., Wakeham, A., Patterson, B., Ohashi, P. S., & Mak, T. W. (1997) · Science · doi:10.1126/science.275.5299.540 · Cited by 583 · see citing works
Chang, H.-C., Sehra, S., Goswami, R., Yao, W., Yu, Q., Stritesky, G. L., Jabeen, R., McKinley, C., Ahyi, A.-N., Han, L., et al. (2010) · Nature Immunology · doi:10.1038/ni.1867 · Cited by 577 · see citing works
Temann, U.-A., Geba, G. P., Rankin, J. A., & Flavell, R. A. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.188.7.1307 · Cited by 452 · see citing works
Pongubala, J. M., Nagulapalli, S., Klemsz, M. J., McKercher, S. R., Maki, R. A., & Atchison, M. L. (1992) · Molecular and Cellular Biology · doi:10.1128/mcb.12.1.368 · Cited by 354 · see citing works
Schmitt, E., Germann, T., Goedert, S., Hoehn, P., Huels, C., Koelsch, S., Kühn, R., Müller, W., Palm, N., & Rüde, E. (1994) · The Journal of Immunology · doi:10.4049/jimmunol.153.9.3989 · Cited by 299 · see citing works
Self-citationBrass, A. L., Kehrli, E., Eisenbeis, C. F., Storb, U., & Singh, H. (1996) · Genes & Development · doi:10.1101/gad.10.18.2335 · Cited by 242 · see citing works
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Lambrecht, B. N., & Hammad, H. (2015) · Nature Immunology · doi:10.1038/ni.3049 · Cited by 1,673 · see citing works
CD4 <sup>+</sup> T Cells: Differentiation and Functions
Luckheeram, R. V., Zhou, R., Verma, A. D., & Xia, B. (2012) · Clinical and Developmental Immunology · doi:10.1155/2012/925135 · Cited by 1,381 · see citing works
Cretney, E., Xin, A., Shi, W., Minnich, M., Masson, F., Miasari, M., Belz, G. T., Smyth, G. K., Busslinger, M., Nutt, S. L., et al. (2011) · Nature Immunology · doi:10.1038/ni.2006 · Cited by 605 · see citing works
Gerlach, K., Hwang, Y., Nikolaev, A., Atreya, R., Dornhoff, H., Steiner, S., Lehr, H.-A., Wirtz, S., Vieth, M., Waisman, A., et al. (2014) · Nature Immunology · doi:10.1038/ni.2920 · Cited by 407 · see citing works
GATA3: a master of many trades in immune regulation
Wan, Y. Y. (2014) · Trends in Immunology · doi:10.1016/j.it.2014.04.002 · Cited by 248 · see citing works
STAT6-dependent regulation of Th9 development
Goswami, R., Jabeen, R., Yagi, R., Pham, D., Zhu, J., Goenka, S., & Kaplan, M. H. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1102840 · Cited by 240 · see citing works
The transcription factor IRF1 dictates the IL-21-dependent anticancer functions of TH9 cells
Végran, F., Berger, H., Boidot, R., Mignot, G., Bruchard, M., Dosset, M., Chalmin, F., Rébé, C., Dérangère, V., Ryffel, B., et al. (2014) · Nature Immunology · doi:10.1038/ni.2925 · Cited by 228 · see citing works
Control of inflammation by integration of environmental cues by regulatory T cells
Chaudhry, A., & Rudensky, A. Y. (2013) · Journal of Clinical Investigation · doi:10.1172/jci57175 · Cited by 183 · see citing works
IL-9 and its receptor are predominantly involved in the pathogenesis of UC
Nalleweg, N., Chiriac, M. T., Podstawa, E., Lehmann, C., Rau, T. T., Atreya, R., Krauss, E., Hundorfean, G., Fichtner-Feigl, S., Hartmann, A., et al. (2015) · Gut · doi:10.1136/gutjnl-2013-305947 · Cited by 181 · see citing works
Kim, I.-K., Kim, B.-S., Koh, C.-H., Seok, J.-W., Park, J.-S., Shin, K.-S., Bae, E.-A., Lee, G.-E., Jeon, H., Cho, J., et al. (2015) · Nature Medicine · doi:10.1038/nm.3922 · Cited by 167 · see citing works
Gcn5 Is Required for PU.1-Dependent IL-9 Induction in Th9 Cells
Goswami, R., & Kaplan, M. H. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1201496 · Cited by 97 · see citing works
“to activate IFN regulatory factor 4 (IRF4) and potentially other factors as part of a transcription factor network in Th9 cells (6, 7).”
BackgroundThe DNA-binding inhibitor Id3 regulates IL-9 production in CD4+ T cells
Nakatsukasa, H., Zhang, D., Maruyama, T., Chen, H., Cui, K., Ishikawa, M., Deng, L., Zanvit, P., Tu, E., Jin, W., et al. (2015) · Nature Immunology · doi:10.1038/ni.3252 · Cited by 80 · see citing works
Jash, A., Sahoo, A., Kim, G.-C., Chae, C.-S., Hwang, J.-S., Kim, J.-E., & Im, S.-H. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.340356 · Cited by 75 · see citing works
Gerlach, K., Popp, V., Wirtz, S., Al-Saifi, R., Gonzalez Acera, M., Atreya, R., Dregelies, T., Vieth, M., Fichtner-Feigl, S., McKenzie, A. N. J., et al. (2022) · Journal of Crohn's and Colitis · doi:10.1093/ecco-jcc/jjac097 · Cited by 25 · see citing works
- Authors
- Staudt, V., Bothur, E., Klein, M., Lingnau, K., Reuter, S., Grebe, N., Gerlitzki, B., Hoffmann, M., Ulges, A., Taube, C., Dehzad, N., Becker, M., Stassen, M., Steinborn, A., Lohoff, M., Schild, H., Schmitt, E., & Bopp, T.
- Affiliations
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Philipps University of Marburg (DE)
- Intercell (Austria) (AT)
- Heidelberg University (DE)
- Corresponding author
- Bopp, Tobias
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2010-08
- Volume
- 33
- Issue
- 2
- Pages
- 192-202
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2088275003
- Cited by
- 554
- References
- 9
- Citations by year
- 2026: 14 · 2025: 14 · 2024: 25 · 2023: 30 · 2022: 23 · 2021: 27 · 2020: 31 · 2019: 32 · 2018: 46 · 2017: 42 · 2016: 53 · 2015: 42 · 2014: 46 · 2013: 49 · 2012: 45
- FWCI
- 17.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Physiology › Asthma and respiratory diseases
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- IRF4, Th9 cells, IL-9, CD4+ T cells, T helper cell differentiation, asthma, transcriptional regulation
- MeSH terms
- Interferon Regulatory Factor-4, Animals, Asthma, Cell Differentiation, Cells, Cultured, T-Lymphocytes, Helper-Inducer, Humans, Mice, Inbred C57BL, Promoter Regions, Genetic, Protein Binding, Interleukin-9, Mice, Knockout, RNA, Small Interfering, Interferon Regulatory Factors, Mice
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