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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 LU ; Vecchio, Federica ; Dwivedi, Om Prakash ; Kvist, Jouni ; Balboa, Diego ; Saarimäki-Vire, Jonna and Montaser, Hossam , et al. (2022) In Nature Communications 13(1).
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Interferon-alpha/pharmacology, Diabetes Mellitus, Type 1/genetics, TYK2 Kinase/genetics, Proto-Oncogene Proteins p21(ras)/metabolism, Insulins/metabolism
in
Nature Communications
volume
13
issue
1
article number
6363
publisher
Nature Publishing Group
external identifiers
  • pmid:36289205
  • scopus:85140650194
ISSN
2041-1723
DOI
10.1038/s41467-022-34069-z
language
English
LU publication?
yes
additional info
© 2022. The Author(s).
id
157c8aea-383a-426b-827e-946b87618fd9
date added to LUP
2022-10-30 11:28:38
date last changed
2024-06-13 22:10:45
@article{157c8aea-383a-426b-827e-946b87618fd9,
  abstract     = {{<p>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.</p>}},
  author       = {{Chandra, Vikash and Ibrahim, Hazem and Halliez, Clémentine and Prasad, Rashmi B and Vecchio, Federica and Dwivedi, Om Prakash and Kvist, Jouni and Balboa, Diego and Saarimäki-Vire, Jonna and Montaser, Hossam and Barsby, Tom and Lithovius, Väinö and Artner, Isabella and Gopalakrishnan, Swetha and Groop, Leif and Mallone, Roberto and Eizirik, Decio L and Otonkoski, Timo}},
  issn         = {{2041-1723}},
  keywords     = {{Humans; Interferon-alpha/pharmacology; Diabetes Mellitus, Type 1/genetics; TYK2 Kinase/genetics; Proto-Oncogene Proteins p21(ras)/metabolism; Insulins/metabolism}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α}},
  url          = {{http://dx.doi.org/10.1038/s41467-022-34069-z}},
  doi          = {{10.1038/s41467-022-34069-z}},
  volume       = {{13}},
  year         = {{2022}},
}