Transcription and splicing regulation by NLRC5 shape the interferon response in human pancreatic β cells
Florian Szymczak, Maria Inês Alvelos, Sandra Marín‐Cañas, Ângela Castela, Stéphane Demine, Máikel L. Colli, Anne Op De Beeck, Sofia Thomaidou, Lorella Marselli, Arnaud Zaldumbide, Piero Marchetti, Décio L. Eizirik
Abstract
IFNα is a key regulator of the dialogue between pancreatic β cells and the immune system in early type 1 diabetes (T1D). IFNα 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 IFNα 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 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 IFNα on alternative splicing, a generator of β cell neoantigens, suggesting that it is a central player of the effects of IFNα on β cells that contribute to trigger and amplify autoimmunity in T1D.