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IκBζ regulates TH17 development by cooperating with ROR nuclear receptors

Nature volume 464, pages 1381–1385 (2010)Cite this article

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Abstract

Interleukin (IL)-17-producing helper T (TH17) cells are a distinct T-cell subset characterized by its pathological role in autoimmune diseases1,2,3. IL-6 and transforming growth factor-β (TGF-β) induce TH17 development, in which the orphan nuclear receptors, RORγt and RORα, have an indispensable role4,5,6. However, in the absence of IL-6 and TGF-β, the ectopic expression of RORγt or RORα leads to only a modest IL-17 production5,7,8. Here we identify a nuclear IκB family member, IκBζ (encoded by the Nfkbiz gene), as a transcription factor required for TH17 development in mice. The ectopic expression of IκBζ in naive CD4+ T cells together with RORγt or RORα potently induces TH17 development, even in the absence of IL-6 and TGF-β. Notably, Nfkbiz-/- mice have a defect in TH17 development and a resistance to experimental autoimmune encephalomyelitis (EAE). The T-cell-intrinsic function of IκBζ was clearly demonstrated by the resistance to EAE of the Rag2-/- mice into which Nfkbiz-/- CD4+ T cells were transferred. In cooperation with RORγt and RORα, IκBζ enhances Il17a expression by binding directly to the regulatory region of the Il17a gene. This study provides evidence for the transcriptional mechanisms underlying TH17 development and points to a molecular basis for a novel therapeutic strategy against autoimmune disease.

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Figure 1: Nfkbiz-/- mice are resistant to EAE owing to a CD4+ T-cell-intrinsic defect in TH17 development.
Figure 2: Targeted disruption of the Nfkbiz gene results in impaired TH17 development.
Figure 3: Ectopic expression of IκBζ facilitates TH17 development.
Figure 4: IκBζ and ROR nuclear receptors cooperatively activate the Il17a promoter and facilitate TH17 development.

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Acknowledgements

We are grateful to Y. Iwakura and T. Kitamura for providing Il17a-/- mice and retrovirus vectors, respectively. We also thank M. Shinohara, T. Negishi-Koga, M. Asagiri, T. Nakashima, N. Komatsu, M. Ohba, Y. Kunisawa, Y. Suzuki, S. Miyakoshi and T. Kunigami for discussion and assistance. This work was supported in part by Grant-in-Aid for Creative Scientific Research from the Japan Society for the Promotion of Science (JSPS), Grant-in-Aid for Challenging Exploratory Research from JSPS, Grant-in-Aid for JSPS Fellows, Grants-in-Aid for GCOE Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), and ERATO, Takayanagi Osteonetwork Project from JST. It was also supported by grants from the Intramural Research Program of the NIEHS (Z01-ES-101586) (to A.M.J.), Takeda Life Science Foundation and Yokoyama Foundation for Clinical Pharmacology and the Ichiro Kanehara Foundation. Ka.O. is supported by JSPS Research Fellowships for Young Scientists.

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Authors and Affiliations

  1. Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University,

    Kazuo Okamoto, Masatsugu Oh-hora & Hiroshi Takayanagi

  2. Global Center of Excellence (GCOE) Program, International Research Center for Molecular Science in Tooth and Bone Diseases,,

    Kazuo Okamoto, Masatsugu Oh-hora & Hiroshi Takayanagi

  3. Japan Science and Technology Agency (JST), ERATO, Takayanagi Osteonetwork Project, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan ,

    Kazuo Okamoto & Hiroshi Takayanagi

  4. Medical Top Track Program, Medical Research Institute, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8510, Japan ,

    Yoshiko Iwai

  5. Department of Microbiology and Immunology, Laboratory of Immune Regulation, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, 2-2, Yamada-oka, Suita, Osaka 565-0871, Japan,

    Masahiro Yamamoto

  6. Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8519, Japan,

    Tomohiro Morio

  7. Department of Hard Tissue Engineering (Pharmacology), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan,

    Kazuhiro Aoki & Keiichi Ohya

  8. Division of Intramural Research, Cell Biology Section, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive Research Triangle Park, North Carolina 27709, USA,

    Anton M. Jetten

  9. Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Yamada-oka 3-1, Suita, Osaka 565-0871, Japan ,

    Shizuo Akira

  10. Laboratory of Cell Recognition and Response, Graduate School of Life Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan ,

    Tatsushi Muta

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Contributions

Ka.O. performed all of the experiments, interpreted the results and prepared the manuscript. Y.I. contributed to dendritic cells experiments and T-cell transfer experiments. M.O. contributed to study design and manuscript preparation. M.Y., A.M.J. and S.A. provided genetically modified mice and advice on data analysis. To.M. provided advice on project planning and data interpretation. K.A. and Ke.O. supported the experiments using Nfkb1-/- mice. Ta.M. provided genetically modified mice and the plasmids, and advised on project planning. H.T. directed the project and wrote the manuscript.

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Correspondence to Hiroshi Takayanagi.

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The authors declare no competing financial interests.

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Okamoto, K., Iwai, Y., Oh-hora, M. et al. IκBζ regulates TH17 development by cooperating with ROR nuclear receptors. Nature 464, 1381–1385 (2010). https://doi.org/10.1038/nature08922

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