The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α

Chandra, Vikash; Ibrahim, Hazem; Halliez, Clémentine; Prasad, Rashmi B.; Vecchio, Federica; Dwivedi, Om Prakash; Kvist, Jouni; Balboa, Diego; Saarimäki-Vire, Jonna; Montaser, Hossam; Barsby, Tom; Lithovius, Väinö; Artner, Isabella; Gopalakrishnan, Swetha; Groop, Leif; Mallone, Roberto; Eizirik, Décio L.; Otonkoski, Timo

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dc.contributor.author	Chandra, Vikash
dc.contributor.author	Ibrahim, Hazem
dc.contributor.author	Halliez, Clémentine
dc.contributor.author	Prasad, Rashmi B.
dc.contributor.author	Vecchio, Federica
dc.contributor.author	Dwivedi, Om Prakash
dc.contributor.author	Kvist, Jouni
dc.contributor.author	Balboa, Diego
dc.contributor.author	Saarimäki-Vire, Jonna
dc.contributor.author	Montaser, Hossam
dc.contributor.author	Barsby, Tom
dc.contributor.author	Lithovius, Väinö
dc.contributor.author	Artner, Isabella
dc.contributor.author	Gopalakrishnan, Swetha
dc.contributor.author	Groop, Leif
dc.contributor.author	Mallone, Roberto
dc.contributor.author	Eizirik, Décio L.
dc.contributor.author	Otonkoski, Timo
dc.date.accessioned	2023-01-24T07:20:00Z
dc.date.available	2023-01-24T07:20:00Z
dc.date.issued	2022
dc.identifier.citation	Chandra 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-z
dc.identifier.issn	2041-1723
dc.identifier.uri	http://hdl.handle.net/10230/55413
dc.description.abstract	Type 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.
dc.description.sponsorship	We gratefully acknowledge Dr. Fatoumata Samassa for help with cytotoxicity assays. We thank Jarkko Ustinov for the insulin and c-peptide ELISA measurements. S. Eurola, H. Grym, and A. Laitinen are thanked for expert technical support. We thank FIMM Single Cell Analytics unit (supported by HiLIFE and Biocentre Finland) for single cell RNA sequencing services. We want to acknowledge the participants and investigators of the FinnGen study. T.O. acknowledges the funding provided by the Academy of Finland (MetaStem Center of Excellence grant 312437), the Novo Nordisk Foundation and the Sigrid Juselius Foundation. R.M. acknowledges the support of the Agence Nationale de la Recherche (ANR-19-CE15-0014-01) and the Fondation pour la Recherche Medicale (EQU20193007831). C.H. was funded by an Année Recherche fellowship of the Paris Saclay University. F.V. was funded by an international PhD fellowship of the IdEx Université de Paris. R.B.P. acknowledges the funding by Hjelt foundation, Crafoord foundation (2020089) and Swedish Research Council (2021-02623). D.L.E. acknowledges the support of grants from the Welbio-FNRS (Fonds National de la Recherche Scientifique; WELBIO-CR-2019C-04), Belgium; the Innovate2CureType1—Dutch Diabetes Research Foundation (DDRF), Holland; the Juvenile Diabetes Foundation (JDRF; 2-SRA-2019-834-S-B); the NIH (HIRN-CBDS) grant U01 DK127786, USA. D.L.E., T.O., and R.M. acknowledge support from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreements No 115797 (INNODIA) and 945268 (INNODIA HARVEST), supported by the European Union’s Horizon 2020 research and innovation programme. These Joint Undertakings receive support from the Union’s Horizon 2020 research and innovation programme and “EFPIA”, “JDRF” and “The Leona M. and Harry B. Helmsley Charitable Trust”.
dc.format.mimetype	application/pdf
dc.language.iso	eng
dc.publisher	Nature Research
dc.relation.ispartof	Nat Commun. 2022 Oct 26;13(1):6363
dc.rights	© 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/.
dc.rights.uri	http://creativecommons.org/licenses/by/4.0/
dc.title	The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α
dc.type	info:eu-repo/semantics/article
dc.identifier.doi	http://dx.doi.org/10.1038/s41467-022-34069-z
dc.subject.keyword	Cellular immunity
dc.subject.keyword	Disease model
dc.subject.keyword	Stem-cell differentiation
dc.subject.keyword	Type 1 diabetes
dc.relation.projectID	info:eu-repo/grantAgreement/EC/H2020/115797
dc.relation.projectID	info:eu-repo/grantAgreement/EC/H2020/945268
dc.rights.accessRights	info:eu-repo/semantics/openAccess
dc.type.version	info:eu-repo/semantics/publishedVersion