期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-34069-z
关键词
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资金
- HiLIFE
- Biocentre Finland
- Academy of Finland (MetaStem Center of Excellence) [312437]
- Novo Nordisk Foundation
- Sigrid Juselius Foundation
- Agence Nationale de la Recherche [ANR-19-CE15-0014-01]
- Fondation pour la Recherche Medicale [EQU20193007831]
- Annee Recherche fellowship of the Paris Saclay University - IdEx Universite de Paris
- Hjelt foundation
- Crafoord foundation [2020089]
- Swedish Research Council [2021-02623]
- Welbio-FNRS (Fonds National de la Recherche Scientifique), Belgium [WELBIO-CR-2019C-04]
- Innovate2CureType1-Dutch Diabetes Research Foundation (DDRF), Holland
- Juvenile Diabetes Foundation (JDRF) [2-SRA-2019-834-S-B]
- NIH (HIRN-CBDS), USA [U01 DK127786]
- Innovative Medicines Initiative 2 Joint, (INNODIA) [115797]
- INNODIA HARVEST [945268]
- European Union's Horizon 2020 research and innovation programme
- EFPIA
- JDRF
- Leona M. and Harry B. Helmsley Charitable Trust
- Swedish Research Council [2021-02623] Funding Source: Swedish Research Council
- Academy of Finland (AKA) [312437, 312437] Funding Source: Academy of Finland (AKA)
The TYK2 gene is crucial in the development of type 1 diabetes. In this study, the researchers demonstrate that TYK2 regulates the development of beta-cells and inhibiting TYK2 in the islets enhances their survival against CD8(+) T-cell cytotoxicity. This finding highlights TYK2 as a potential therapeutic target to halt the progression of type 1 diabetes.
The TYK2 gene is associated with development of type 1 diabetes. Here the authors show that TYK2 regulates beta-cell development, but at the same time TYK2 inhibition in the islets prevents IFN alpha responses and enhances their survival against CD8(+) T-cell cytotoxicity; representing a potent therapeutic target to halt T1D progression. Type 1 diabetes (T1D) is an autoimmune disease that results in the destruction of insulin producing pancreatic beta-cells. One of the genes associated with T1D is TYK2, which encodes a Janus kinase with critical roles in type-Iota interferon (IFN-Iota) mediated intracellular signalling. To study the role of TYK2 in beta-cell development and response to IFN alpha, we generated TYK2 knockout human iPSCs and directed them into the pancreatic endocrine lineage. Here we show that loss of TYK2 compromises the emergence of endocrine precursors by regulating KRAS expression, while mature stem cell-islets (SC-islets) function is not affected. In the SC-islets, the loss or inhibition of TYK2 prevents IFN alpha-induced antigen processing and presentation, including MHC Class Iota and Class Iota Iota expression, enhancing their survival against CD8(+) T-cell cytotoxicity. These results identify an unsuspected role for TYK2 in beta-cell development and support TYK2 inhibition in adult beta-cells as a potent therapeutic target to halt T1D progression.
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