The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.
IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype
Open accessAbstract
Differentiation of murine T-helper (Th) 17 cells is induced by antigenic stimulation and the sequential action of the cytokines IL-6, IL-21, and IL-23, along with TGFβ. Current dogma proposes that IL-6 induces IL-21, which, in a STAT3-dependent manner, amplifies its own transcription, contributes to IL-17 production, and, moreover, promotes the expression of the IL-23 receptor. This, in turn, prepares cells for IL-23-mediated stabilization of the Th17 phenotype. Here we demonstrate that these effects of IL-21 on Th17 differentiation are completely dependent on IFN regulatory factor 4 (IRF4). After culturing in the presence of IL-21 plus TGFβ, IRF4-deficient ( Irf4 −/− ) Th cells showed a profound intrinsic defect in IL-17 production and in the autocrine IL-21 loop. Likewise, the levels of IL-23 receptor and the lineage-specific orphan nuclear receptors RORα and RORγt were diminished, whereas the T regulatory (Treg) transcription factor forkhead box P3 (Foxp3) was strongly up-regulated, consistent with the reciprocal relationship between Th17 and Treg development. Despite this loss of IL-21 functions, IL-21-induced STAT3 activation was unimpaired and induced normal Socs3 expression. Forced expression of Foxp3 in WT cells inhibited IL-21-mediated IL-17 production, suggesting that the increase in Foxp3 contributes to the Irf4 −/− phenotype. Additionally, the low levels of RORα and RORγt are also partially responsible, because simultaneous overexpression of both proteins restored IL-17 production in Irf4 −/− cells to some extent. These data highlight IRF4 as a decisive factor during the IL-21-mediated steps of Th17 development by influencing the balance of Foxp3, RORα, and RORγt.
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Cites
Control of Regulatory T Cell Development by the Transcription Factor Foxp3
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Transforming growth factor-β induces development of the TH17 lineage
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Collaborative Association Study of Psoriasis (CASP), Tsoi, L. C., Genetic Analysis of Psoriasis Consortium, Psoriasis Association Genetics Extension, Wellcome Trust Case Control Consortium 2, Spain, S. L., Knight, J., Ellinghaus, E., Stuart, P. E., Capon, F., et al. (2012) · Nature Genetics · doi:10.1038/ng.2467 · Cited by 1,024
Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells
Staudt, V., Bothur, E., Klein, M., Lingnau, K., Reuter, S., Grebe, N., Gerlitzki, B., Hoffmann, M., Ulges, A., Taube, C., et al. (2010) · Immunity · doi:10.1016/j.immuni.2010.07.014 · Cited by 554
Self-citationThe plasticity of human Treg and Th17 cells and its role in autoimmunity
Kleinewietfeld, M., & Hafler, D. A. (2013) · Seminars in Immunology · doi:10.1016/j.smim.2013.10.009 · Cited by 389
Glasmacher, E., Agrawal, S., Chang, A. B., Murphy, T. L., Zeng, W., Vander Lugt, B., Khan, A. A., Ciofani, M., Spooner, C. J., Rutz, S., et al. (2012) · Science · doi:10.1126/science.1228309 · Cited by 361
Metadata
- Authors
- Huber, M., Brüstle, A., Reinhard, K., Guralnik, A., Walter, G., Mahiny, A., von Löw, E., & Lohoff, M.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2008-12-30
- Volume
- 105
- Issue
- 52
- Pages
- 20846-20851
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2058950182
- Cited by
- 282
- References
- 10
- FWCI
- 9.33
- Type
- journal article
- Language
- en
- Open access
- green
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- Huber, M., Brüstle, A., Reinhard, K., Guralnik, A., Walter, G., Mahiny, A., von Löw, E., & Lohoff, M. (2008). IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.0809077106
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