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

Vikash Chandra (), Hazem Ibrahim, Clémentine Halliez, Rashmi B. Prasad, Federica Vecchio, Om Prakash Dwivedi, Jouni Kvist, Diego Balboa, Jonna Saarimäki-Vire, Hossam Montaser, Tom Barsby, Väinö Lithovius, Isabella Artner, Swetha Gopalakrishnan, Leif Groop, Roberto Mallone, Decio L. Eizirik and Timo Otonkoski ()
Additional contact information
Vikash Chandra: University of Helsinki
Hazem Ibrahim: University of Helsinki
Clémentine Halliez: Université Paris Cité, Institut Cochin, CNRS, INSERM
Rashmi B. Prasad: Lund University, CRC
Federica Vecchio: Université Paris Cité, Institut Cochin, CNRS, INSERM
Om Prakash Dwivedi: Helsinki University
Jouni Kvist: University of Helsinki
Diego Balboa: University of Helsinki
Jonna Saarimäki-Vire: University of Helsinki
Hossam Montaser: University of Helsinki
Tom Barsby: University of Helsinki
Väinö Lithovius: University of Helsinki
Isabella Artner: Lund University
Swetha Gopalakrishnan: University of Helsinki
Leif Groop: Helsinki University
Roberto Mallone: Université Paris Cité, Institut Cochin, CNRS, INSERM
Decio L. Eizirik: Université Libre de Bruxelles
Timo Otonkoski: University of Helsinki

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34069-z

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