Chandra, VikashIbrahim, HazemHalliez, ClémentinePrasad, Rashmi B.Vecchio, FedericaDwivedi, Om PrakashKvist, JouniBalboa, DiegoSaarimäki-Vire, JonnaMontaser, HossamBarsby, TomLithovius, VäinöArtner, IsabellaGopalakrishnan, SwethaGroop, LeifMallone, RobertoEizirik, Décio L.Otonkoski, Timo2023-01-242023-01-242022Chandra V, Ibrahim H, Halliez C, Prasad RB, Vecchio F, Dwivedi OP, Kvist J, Balboa D, Saarimäki-Vire J, Montaser H, Barsby T, Lithovius V, Artner I, Gopalakrishnan S, Groop L, Mallone R, Eizirik DL, Otonkoski T. The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α. Nat Commun. 2022 Oct 26;13(1):6363. DOI: 10.1038/s41467-022-34069-z2041-1723http://hdl.handle.net/10230/55413Type 1 diabetes (T1D) is an autoimmune disease that results in the destruction of insulin producing pancreatic β-cells. One of the genes associated with T1D is TYK2, which encodes a Janus kinase with critical roles in type-Ι interferon (IFN-Ι) mediated intracellular signalling. To study the role of TYK2 in β-cell development and response to IFNα, 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 IFNα-induced antigen processing and presentation, including MHC Class Ι and Class ΙΙ expression, enhancing their survival against CD8+ T-cell cytotoxicity. These results identify an unsuspected role for TYK2 in β-cell development and support TYK2 inhibition in adult β-cells as a potent therapeutic target to halt T1D progression.application/pdfeng© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-022-34069-zCellular immunityDisease modelStem-cell differentiationType 1 diabetesinfo:eu-repo/semantics/openAccess