TYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetes
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-obe...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-45573-9 |
| _version_ | 1827326925744373760 |
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| author | Keiichiro Mine Seiho Nagafuchi Satoru Akazawa Norio Abiru Hitoe Mori Hironori Kurisaki Kazuya Shimoda Yasunobu Yoshikai Hirokazu Takahashi Keizo Anzai |
| author_facet | Keiichiro Mine Seiho Nagafuchi Satoru Akazawa Norio Abiru Hitoe Mori Hironori Kurisaki Kazuya Shimoda Yasunobu Yoshikai Hirokazu Takahashi Keizo Anzai |
| author_sort | Keiichiro Mine |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T14:52:32Z |
| format | Article |
| id | doaj.art-5edae9b94e074d8ca0993562feea1375 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:52:32Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-5edae9b94e074d8ca0993562feea13752024-03-05T19:37:19ZengNature PortfolioNature Communications2041-17232024-02-0115111410.1038/s41467-024-45573-9TYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetesKeiichiro Mine0Seiho Nagafuchi1Satoru Akazawa2Norio Abiru3Hitoe Mori4Hironori Kurisaki5Kazuya Shimoda6Yasunobu Yoshikai7Hirokazu Takahashi8Keizo Anzai9Division of Metabolism and Endocrinology, Faculty of Medicine, Saga UniversityDivision of Metabolism and Endocrinology, Faculty of Medicine, Saga UniversityDepartment of Endocrinology and Metabolism, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical SciencesDepartment of Endocrinology and Metabolism, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical SciencesDivision of Metabolism and Endocrinology, Faculty of Medicine, Saga UniversityDepartment of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu UniversityDivision of Hematology, Diabetes, and Endocrinology, Department of Internal Medicine, Faculty of Medicine, University of MiyazakiDivision of Host Defense, Medical Institute of Bioregulation, Kyushu UniversityDivision of Metabolism and Endocrinology, Faculty of Medicine, Saga UniversityDivision of Metabolism and Endocrinology, Faculty of Medicine, Saga UniversityAbstract 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.https://doi.org/10.1038/s41467-024-45573-9 |
| spellingShingle | Keiichiro Mine Seiho Nagafuchi Satoru Akazawa Norio Abiru Hitoe Mori Hironori Kurisaki Kazuya Shimoda Yasunobu Yoshikai Hirokazu Takahashi Keizo Anzai TYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetes Nature Communications |
| title | TYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetes |
| title_full | TYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetes |
| title_fullStr | TYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetes |
| title_full_unstemmed | TYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetes |
| title_short | TYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetes |
| title_sort | tyk2 signaling promotes the development of autoreactive cd8 cytotoxic t lymphocytes and type 1 diabetes |
| url | https://doi.org/10.1038/s41467-024-45573-9 |
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