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

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 and Yoichiro Iwakura ()
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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
Harumichi Ishigame: Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo
Shigeru Kakuta: Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo
Soo-hyun Chung: Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo
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
Sachiko Kubo: Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo
Yang Liu: Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo
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
Yoichiro Iwakura: Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8464

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