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

Author

Listed:
  • 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
    Helsinki University)

  • Federica Vecchio

    (Université Paris Cité, Institut Cochin, CNRS, INSERM)

  • Om Prakash Dwivedi

    (Helsinki University)

  • Jouni Kvist

    (University of Helsinki)

  • Diego Balboa

    (University of Helsinki
    The Barcelona Institute of Science and Technology)

  • 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
    Cochin Hospital)

  • Decio L. Eizirik

    (Université Libre de Bruxelles)

  • Timo Otonkoski

    (University of Helsinki
    Helsinki University Hospital)

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.

Suggested Citation

  • 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 & Väin, 2022. "The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34069-z
    DOI: 10.1038/s41467-022-34069-z
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    1. Kenichi Izumi & Keiichiro Mine & Yoshitaka Inoue & Miho Teshima & Shuichiro Ogawa & Yuji Kai & Toshinobu Kurafuji & Kanako Hirakawa & Daiki Miyakawa & Haruka Ikeda & Akari Inada & Manami Hara & Hisaka, 2015. "Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes," Nature Communications, Nature, vol. 6(1), pages 1-10, November.
    2. Sergey Nejentsev & Joanna M. M. Howson & Neil M. Walker & Jeffrey Szeszko & Sarah F. Field & Helen E. Stevens & Pamela Reynolds & Matthew Hardy & Erna King & Jennifer Masters & John Hulme & Lisa M. Ma, 2007. "Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A," Nature, Nature, vol. 450(7171), pages 887-892, December.
    3. Adrian Veres & Aubrey L. Faust & Henry L. Bushnell & Elise N. Engquist & Jennifer Hyoje-Ryu Kenty & George Harb & Yeh-Chuin Poh & Elad Sintov & Mads Gürtler & Felicia W. Pagliuca & Quinn P. Peterson &, 2019. "Charting cellular identity during human in vitro β-cell differentiation," Nature, Nature, vol. 569(7756), pages 368-373, May.
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    Cited by:

    1. Keiichiro Mine & Seiho Nagafuchi & Satoru Akazawa & Norio Abiru & Hitoe Mori & Hironori Kurisaki & Kazuya Shimoda & Yasunobu Yoshikai & Hirokazu Takahashi & Keizo Anzai, 2024. "TYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetes," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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