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The development of inflammatory TH-17 cells requires interferon-regulatory factor 4

Nature Immunology volume 8, pages 958–966 (2007)Cite this article

Abstract

Interferon-regulatory factor 4 (IRF4) is essential for the development of T helper type 2 cells. Here we show that IRF4 is also critical for the generation of interleukin 17–producing T helper cells (TH-17 cells), which are associated with experimental autoimmune encephalomyelitis. IRF4-deficient (Irf4−/−) mice did not develop experimental autoimmune encephalomyelitis, and T helper cells from such mice failed to differentiate into TH-17 cells. Transfer of wild-type T helper cells into Irf4−/− mice rendered the mice susceptible to experimental autoimmune encephalomyelitis. Irf4−/− T helper cells had less expression of RORγt and more expression of Foxp3, transcription factors important for the differentiation of TH-17 and regulatory T cells, respectively. Altered regulation of both transcription factors contributed to the phenotype of Irf4−/− T helper cells. Our data position IRF4 at the center of T helper cell development, influencing not only T helper type 2 but also TH-17 differentiation.

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Figure 1: Irf4−/− T helper cells do not differentiate into TH-17 cells in vitro.
Figure 2: IRF4-specific siRNA blocks TH-17 differentiation of wild-type (Irf4+/+) cells.
Figure 3: Irf4−/− mice are protected from EAE.
Figure 4: A differentiation defect intrinsic to T helper cells mediates the EAE resistance of Irf4−/− mice.
Figure 5: Relationship between IRF4 and RORγt expression.
Figure 6: Relationship between IRF4 and Foxp3 expression.

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Acknowledgements

We thank D. Littman for RORγt-expressing retrovirus; A. Scheffold (Deutsches Rheuma-Forschungszentrum Berlin) for help with siRNA experiments; R. Volkmer (Institut für Medizinische Immunologie, Charité-Universitätsmedizin Berlin) MOG peptide; P. Sack for technical assistance; and M. Saunders for scientific editing. Supported by the Deutsche Forschungsgemeinschaft (LO 396, TR SFB 6044 and GRK 767 to M.L.) and the Gemeinnützige Hertie-Stiftung (1.319.110/03/03 to T.K.).

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Authors and Affiliations

  1. Institut für Medizinische Mikrobiologie und Krankenhaushygiene, Marburg, 35043, Germany

    Anne Brüstle, Magdalena Huber, Christine Rosenplänter & Michael Lohoff

  2. Institut für Immunologie, Universitätsklinikum Jena, Jena, 07740, Germany

    Sylvia Heink & Thomas Kamradt

  3. Institut für Neuropathologie, Universität Göttingen, Göttingen, 37075, Germany

    Christine Stadelmann

  4. Institut für Immunologie, Marburg, 35043, Germany

    Philipp Yu

  5. Advanced Medical Discovery Institute, University of Toronto, Toronto, M5G2C1, Ontario, Canada

    Enrico Arpaia & Tak W Mak

  6. Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, M5G2C1, Ontario, Canada

    Tak W Mak

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  1. Anne Brüstle
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Contributions

A.B. did the in vitro experiments with assistance from M.H.,C.R., P.Y. and E.A.; S.H. did the in vivo and ex vivo experiments; C.S. did the histology; and T.W.M.,T.K. and M.L. provided advice and overall direction and supervised project planning and execution.

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Correspondence to Michael Lohoff.

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The authors declare no competing financial interests.

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Supplementary Figures 1–4, Tables 1 and 2, and Methods (PDF 971 kb)

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Brüstle, A., Heink, S., Huber, M. et al. The development of inflammatory TH-17 cells requires interferon-regulatory factor 4. Nat Immunol 8, 958–966 (2007). https://doi.org/10.1038/ni1500

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