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

Keiichiro Mine (), Seiho Nagafuchi, Satoru Akazawa, Norio Abiru, Hitoe Mori, Hironori Kurisaki, Kazuya Shimoda, Yasunobu Yoshikai, Hirokazu Takahashi and Keizo Anzai
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Keiichiro Mine: Saga University
Seiho Nagafuchi: Saga University
Satoru Akazawa: Nagasaki University Graduate School of Biomedical Sciences
Norio Abiru: Nagasaki University Graduate School of Biomedical Sciences
Hitoe Mori: Saga University
Hironori Kurisaki: Kyushu University
Kazuya Shimoda: University of Miyazaki
Yasunobu Yoshikai: Kyushu University
Hirokazu Takahashi: Saga University
Keizo Anzai: Saga University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45573-9

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