IFNa is a key regulator of the dialogue between pancreatic 0 cells and the immune system in early type 1 diabetes (T1D). IFNa up-regulates HLA class I expression in human 0 cells, fostering... Show moreIFNa is a key regulator of the dialogue between pancreatic 0 cells and the immune system in early type 1 diabetes (T1D). IFNa up-regulates HLA class I expression in human 0 cells, fostering autoantigen presentation to the immune system. We observed by bulk and single-cell RNA sequencing that exposure of human induced pluripotentderived islet-like cells to IFNa induces expression of HLA class I and of other genes involved in antigen presentation, including the transcriptional activator NLRC5. We next evaluated the global role of NLRC5 in human insulinproducing EndoC-0H1 and human islet cells by RNA sequencing and targeted gene/protein determination. NLRC5 regulates expression of HLA class I, antigen presentation-related genes, and chemokines. NLRC5 also mediates the effects of IFNa on alternative splicing, a generator of 0 cell neoantigens, suggesting that it is a central player of the effects of IFNa on 0 cells that contribute to trigger and amplify autoimmunity in T1D. Show less
