RNA editing deficiency models differential immunogenicity of pancreatic α- and β-cells

Objective: A longstanding question in type 1 diabetes (T1D) research pertains to the selective loss of β-cells whilst neighboring islet α-cells remain unharmed. We examined molecular mechanisms that may underly this differential vulnerability, by investigating the role of RNA editing, a cellular process that prevents double-stranded RNA (dsRNA)-mediated interferon response, in mouse α- and β-cells. Methods: The enzyme responsible for RNA editing, Adar, was selectively deleted in vivo in mouse β-cells, α-cells, or in both cell types. Subsequent analyses were performed to investigate the impact of deficient RNA editing in α- or β-cells on the interferon response, islet inflammation, cell viability and metabolic outcomes. Results: Mosaic disruption of the Adar gene in mouse β-cells triggers a massive interferon response, islet inflammation and mutant β-cell destruction. Surprisingly, wild type β-cells are also eliminated, whereas neighboring α-cells are unaffected. α-cell Adar deletion leads to only a slight elevation in interferon signature and does not elicit inflammation nor a metabolic phenotype. Concomitant deletion of Adar in α- and β-cells leads to elimination of both cell populations, suggesting that in contrast to β-cells, α-cell death requires both cell autonomous deficiency in RNA editing and exogenous cytokines. Conclusions: We demonstrate differential sensitivity of mouse α- and β-cells to deficient RNA editing. The resistance of α-cells to RNA editing deficiency and to cytokines mirrors their persistence in T1D, and constitutes a molecularly defined model of differential islet cell vulnerability.