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

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-I interferon (IFN) mediated intracellular signaling. To study the role of TYK2 in human pancreatic 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 compromised the emergence of endocrine precursors by regulating KRAS expression while mature stem cell islets (SC-islets) function was not affected. In the maturing SC-islets, the loss or inhibition of TYK2 prevented IFNα-induced antigen processing and presentation, including MHC Class I expression in pancreatic endocrine and progenitor cells. Furthermore, in a CD8+ cytotoxic T-cell co-culture model, the survival of β-cells was enhanced by a selective TYK2 inhibitor. These results identify an unsuspected role for TYK2 on β-cell development and support TYK2 inhibition in adult β-cells as a potent therapeutic target to halt T1D progression.