Transcription and splicing regulation by NLRC5 shape the interferon response in human pancreatic β-cells [iPSC scRNAseq]

IFNa is a key regulator of the dialogue between pancreatic β-cells and the immune system in early type 1 diabetes (T1D). IFNa up-regulates HLA class I expression in human β-cells fostering autoantigen presentation to the immune system. We observed by bulk and single cell RNA sequencing that exposure of human induced pluripotent-derived 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 insulin-producing EndoC-βH1 and human islets cells by RNA sequencing and targeted gene/protein determination. NLRC5 regulates expression of HLA class I expression and related genes and of chemokines. NLRC5 also mediates the effects of IFNa on alternative splicing, a generator of β-cell neoantigens, suggesting that it is a central mediator of the effects of IFNa on β-cells that contribute to trigger and amplify autoimmunity in T1D. Comparative gene expression profiling analysis of scRNA-seq data for Islets-like cells exposed, or not, to IFNa