TYK2, a Candidate Gene for Type 1 Diabetes, Modulates Apoptosis and the Innate Immune Response in Human Pancreatic β-Cells

Diabetes. 2015 Nov;64(11):3808-17. doi: 10.2337/db15-0362. Epub 2015 Aug 3.


Pancreatic β-cells are destroyed by an autoimmune attack in type 1 diabetes. Linkage and genome-wide association studies point to >50 loci that are associated with the disease in the human genome. Pathway analysis of candidate genes expressed in human islets identified a central role for interferon (IFN)-regulated pathways and tyrosine kinase 2 (TYK2). Polymorphisms in the TYK2 gene predicted to decrease function are associated with a decreased risk of developing type 1 diabetes. We presently evaluated whether TYK2 plays a role in human pancreatic β-cell apoptosis and production of proinflammatory mediators. TYK2-silenced human β-cells exposed to polyinosinic-polycitidilic acid (PIC) (a mimick of double-stranded RNA produced during viral infection) showed less type I IFN pathway activation and lower production of IFNα and CXCL10. These cells also had decreased expression of major histocompatibility complex (MHC) class I proteins, a hallmark of early β-cell inflammation in type 1 diabetes. Importantly, TYK2 inhibition prevented PIC-induced β-cell apoptosis via the mitochondrial pathway of cell death. The present findings suggest that TYK2 regulates apoptotic and proinflammatory pathways in pancreatic β-cells via modulation of IFNα signaling, subsequent increase in MHC class I protein, and modulation of chemokines such as CXCL10 that are important for recruitment of T cells to the islets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics*
  • Apoptosis / immunology
  • Cell Line
  • Cell Survival / genetics
  • Chemokine CXCL10 / genetics
  • Chemokine CXCL10 / metabolism
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / metabolism
  • Genes, MHC Class I / physiology
  • Genome-Wide Association Study
  • Humans
  • Immunity, Innate / genetics*
  • Insulin-Secreting Cells / immunology
  • Insulin-Secreting Cells / metabolism*
  • Interferon-alpha / genetics
  • Interferon-alpha / metabolism
  • Phosphorylation
  • Polymorphism, Single Nucleotide
  • TYK2 Kinase / genetics*
  • TYK2 Kinase / metabolism


  • Chemokine CXCL10
  • Interferon-alpha
  • TYK2 Kinase
  • TYK2 protein, human