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IL-1 receptor antagonist-deficient mice develop autoimmune arthritis due to intrinsic activation of IL-17-producing CCR2+Vγ6+γδ T cells

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  • Aoi Akitsu

    (Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo
    Graduate School of Science, The University of Tokyo
    Research Fellow of the Japan Society for the Promotion of Science (JSPS)
    Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency)

  • Harumichi Ishigame

    (Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo
    Present address: RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan)

  • Shigeru Kakuta

    (Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo
    Present address: Department of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan)

  • Soo-hyun Chung

    (Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo
    Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science)

  • Satoshi Ikeda

    (Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo)

  • Kenji Shimizu

    (Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo
    Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science)

  • Sachiko Kubo

    (Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo
    Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science)

  • Yang Liu

    (Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo
    Present address: Renji Hospital Clinical Stem Cell Research Center, Shanghai Jiao Tong University School of Medicine, Shang Hai 200127, China)

  • Masayuki Umemura

    (Tropical Biosphere Research Center, University of the Ryukyus)

  • Goro Matsuzaki

    (Tropical Biosphere Research Center, University of the Ryukyus)

  • Yasunobu Yoshikai

    (Research Center for Prevention of Infectious Diseases, Medical Institute of Bioregulation, Kyushu University)

  • Shinobu Saijo

    (Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo
    Present address: Department of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba 263-8522, Japan)

  • Yoichiro Iwakura

    (Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo
    Graduate School of Science, The University of Tokyo
    Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency
    Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science)

Abstract

Interleukin-17 (IL-17)-producing γδ T (γδ17) cells have been implicated in inflammatory diseases, but the underlying pathogenic mechanisms remain unclear. Here, we show that both CD4+ and γδ17 cells are required for the development of autoimmune arthritis in IL-1 receptor antagonist (IL-1Ra)-deficient mice. Specifically, activated CD4+ T cells direct γδ T-cell infiltration by inducing CCL2 expression in joints. Furthermore, IL-17 reporter mice reveal that the Vγ6+ subset of CCR2+ γδ T cells preferentially produces IL-17 in inflamed joints. Importantly, because IL-1Ra normally suppresses IL-1R expression on γδ T cells, IL-1Ra-deficient mice exhibit elevated IL-1R expression on Vγ6+ cells, which play a critical role in inducing them to produce IL-17. Our findings demonstrate a pathogenic mechanism in which adaptive and innate immunity induce an autoimmune disease in a coordinated manner.

Suggested Citation

  • Aoi Akitsu & Harumichi Ishigame & Shigeru Kakuta & Soo-hyun Chung & Satoshi Ikeda & Kenji Shimizu & Sachiko Kubo & Yang Liu & Masayuki Umemura & Goro Matsuzaki & Yasunobu Yoshikai & Shinobu Saijo & Yo, 2015. "IL-1 receptor antagonist-deficient mice develop autoimmune arthritis due to intrinsic activation of IL-17-producing CCR2+Vγ6+γδ T cells," Nature Communications, Nature, vol. 6(1), pages 1-15, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8464
    DOI: 10.1038/ncomms8464
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    Cited by:

    1. Zhengping Huang & Xiaomeng You & Liang Chen & Yan Du & Kailey Brodeur & Hyuk Jee & Qiang Wang & Grace Linder & Roxane Darbousset & Pierre Cunin & Margaret H. Chang & Alexandra Wactor & Brian M. Waufor, 2022. "mTORC1 links pathology in experimental models of Still’s disease and macrophage activation syndrome," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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