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TYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetes

Author

Listed:
  • Keiichiro Mine

    (Saga University
    Kyushu University)

  • Seiho Nagafuchi

    (Saga University)

  • Satoru Akazawa

    (Nagasaki University Graduate School of Biomedical Sciences)

  • Norio Abiru

    (Nagasaki University Graduate School of Biomedical Sciences
    Midori Clinic)

  • Hitoe Mori

    (Saga University)

  • Hironori Kurisaki

    (Kyushu University)

  • Kazuya Shimoda

    (University of Miyazaki)

  • Yasunobu Yoshikai

    (Kyushu University)

  • Hirokazu Takahashi

    (Saga University
    Saga University Hospital, Saga University)

  • Keizo Anzai

    (Saga University)

Abstract

Tyrosine kinase 2 (TYK2), a member of the JAK family, has attracted attention as a potential therapeutic target for autoimmune diseases. However, the role of TYK2 in CD8+ T cells and autoimmune type 1 diabetes (T1D) is poorly understood. In this study, we generate Tyk2 gene knockout non-obese diabetes (NOD) mice and demonstrate that the loss of Tyk2 inhibits the development of autoreactive CD8+ T-BET+ cytotoxic T lymphocytes (CTLs) by impairing IL-12 signaling in CD8+ T cells and the CD8+ resident dendritic cell-driven cross-priming of CTLs in the pancreatic lymph node (PLN). Tyk2-deficient CTLs display reduced cytotoxicity. Increased inflammatory responses in β-cells with aging are dampened by Tyk2 deficiency. Furthermore, treatment with BMS-986165, a selective TYK2 inhibitor, inhibits the expansion of T-BET+ CTLs, inflammation in β-cells and the onset of autoimmune T1D in NOD mice. Thus, our study reveals the diverse roles of TYK2 in driving the pathogenesis of T1D.

Suggested Citation

  • Keiichiro Mine & Seiho Nagafuchi & Satoru Akazawa & Norio Abiru & Hitoe Mori & Hironori Kurisaki & Kazuya Shimoda & Yasunobu Yoshikai & Hirokazu Takahashi & Keizo Anzai, 2024. "TYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetes," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45573-9
    DOI: 10.1038/s41467-024-45573-9
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    References listed on IDEAS

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    1. Vikash Chandra & Hazem Ibrahim & Clémentine Halliez & Rashmi B. Prasad & Federica Vecchio & Om Prakash Dwivedi & Jouni Kvist & Diego Balboa & Jonna Saarimäki-Vire & Hossam Montaser & Tom Barsby & Väin, 2022. "The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Sofia V. Gearty & Friederike Dündar & Paul Zumbo & Gabriel Espinosa-Carrasco & Mojdeh Shakiba & Francisco J. Sanchez-Rivera & Nicholas D. Socci & Prerak Trivedi & Scott W. Lowe & Peter Lauer & Neeman , 2022. "An autoimmune stem-like CD8 T cell population drives type 1 diabetes," Nature, Nature, vol. 602(7895), pages 156-161, February.
    3. Kenichi Izumi & Keiichiro Mine & Yoshitaka Inoue & Miho Teshima & Shuichiro Ogawa & Yuji Kai & Toshinobu Kurafuji & Kanako Hirakawa & Daiki Miyakawa & Haruka Ikeda & Akari Inada & Manami Hara & Hisaka, 2015. "Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes," Nature Communications, Nature, vol. 6(1), pages 1-10, November.
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