IκBη regulates TH 17 development by cooperating with ROR nuclear receptors

Kazuo Okamoto, Yoshiko Iwai, Masatsugu Oh-Hora, Masahiro Yamamoto, Tomohiro Morio, Kazuhiro Aoki, Keiichi Ohya, Anton M. Jetten, Shizuo Akira, Tatsushi Muta, Hiroshi Takayanagi

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    171 Citations (Scopus)

    Abstract

    Interleukin (IL)-17-producing helper T (TH17) cells are a distinct T-cell subset characterized by its pathological role in autoimmune diseases1-3. IL-6 and transforming growth factor-Β (TGF-Β) induce T H 17 development, in which the orphan nuclear receptors, RORγt and RORα, have an indispensable role4-6. 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 IB family member, IB (encoded by the Nfkbiz gene), as a transcription factor required for TH17 development in mice. The ectopic expression of IB in naive CD4+ T cells together with RORγt or RORα potently induces T H 17 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 IB 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, IB 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.

    Original languageEnglish
    Pages (from-to)1381-1385
    Number of pages5
    JournalNature
    Volume464
    Issue number7293
    DOIs
    Publication statusPublished - Apr 29 2010

    All Science Journal Classification (ASJC) codes

    • General

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    Okamoto, K., Iwai, Y., Oh-Hora, M., Yamamoto, M., Morio, T., Aoki, K., Ohya, K., Jetten, A. M., Akira, S., Muta, T., & Takayanagi, H. (2010). IκBη regulates TH 17 development by cooperating with ROR nuclear receptors. Nature, 464(7293), 1381-1385. https://doi.org/10.1038/nature08922