TYK2 regulates human pancreatic beta-cell development and its responses to interferon-alpha [tyk2_scRNAseq]

Type 1 diabetes (T1D) is an autoimmune disease that results in the destruction of insulin producing pancreatic b-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 signalling. To study the role of TYK2 in human pancreatic b-cell development and response to IFNa, we generated TYK2 knockout human iPSCs and directed them into the pancreatic endocrine lineage. Unexpectedly, loss of TYK2 compromised the emergence of endocrine precursors by regulating KRAS expression, however, mature b-cell function was not affected. In the mature stem cell-derived islets, the loss or inhibition of TYK2 prevented IFNa-induced antigen processing and presentation, including MHC Class I expression, enhancing their survival against T-cell cytotoxicity. These results identify an unsuspected role for TYK2 on b-cell development and support TYK2 inhibition in adult b-cells as a potent therapeutic target to halt T1D progression. Overall design: We performed single cell RNA-seq in two stages (S5 & S6) of pancreatic differentiation for CRISPR/Cas9 generated TYK2 KO hiPSC lines and non-edited negative control (WT) samples. We also performed scRNA-seq on same samples (in S6) treated with IFNa.