A mitochondrial ROS-dependent antiviral response promotes β cell resilience and is diminished in donors with type 1 diabetes.

Abstract

Type 1 diabetes (T1D) is a multifactorial disease driven by genetic and environmental factors, including, potentially, viral infection. However, the mechanisms linking infection-associated cytokines to human β cell loss are poorly understood. Here, we coupled in vivo and in vitro imaging with genetic analysis to investigate the impact of interferon α (IFN-α), a cytokine produced during the immune response to viral infection or detection of unedited endogenous double-stranded RNAs, on human β cell physiology. We identified a subset of human β cells that acutely produce reactive oxygen species (ROS) in response to IFN-α and were more prevalent in islets from donors with lower body mass index and HbA1c. RNA sequencing of flow-sorted ROS⁺ and ROS^- populations identified a gene signature predisposing some cells to IFN-α-stimulated ROS production, including genes involved in inflammatory and immune response. IFN-α treatment of human islets in vitro similarly elicited a heterogeneous increase in superoxide production. Parallel analysis of a human β cell line demonstrated that this ROS originated in the mitochondria. Rapid stimulation of key antiviral response genes by IFN-α in human islets was dependent on mitochondrial ROS elevation. Comparison with single-cell RNA sequencing datasets showed that genes up-regulated in ROS-producing cells were enriched in β cells from nondiabetic and autoantibody-positive donors rather than donors with T1D. Overall, our data demonstrate that IFN-α-induced mitochondrial ROS production in healthy human β cells is critical for the acute antiviral response, and impairment of this heterogeneous adaptive response may predict β cell loss during T1D pathogenesis.