Beta Cell Heterogeneity in the Acute Interferon Alpha Response

Abstract

Type 1 diabetes (T1D) is characterized by autoimmune destruction of the insulin-producing β-cells in the pancreatic islet. This autoimmunity is hypothesized to result from a combination of genetic and environmental factors, with early childhood viral infection being a leading hypothesis for the latter. In response to viral infections, the innate immune system produces various cytokines, including interferon alpha (IFN-α), which has long been implicated in T1D pathogenesis. Our study explores how IFN-α influences human β-cell function, particularly its role in reactive oxygen species (ROS) production—signaling molecules essential for normal β-cell function but detrimental in excess. Using intravital microscopy and a β-cell-specific ROS biosensor, we identified a subset of β-cells that rapidly produce ROS in response to IFN-α. Interestingly, phenotyping data from the donors indicated that healthier β-cells were more likely to exhibit this response. In vitro experiments confirmed that IFN-α drives mitochondrial superoxide production in a subset human of β-cells, prompting us to investigate the molecular basis of this phenomenon. RNA sequencing of sorted IFN-α–treated cells revealed an upregulation of immune-related genes, and comparison with single-cell datasets showed that these genes are more highly expressed in β-cells from healthy individuals than those with T1D. These findings suggest that IFN-α–induced ROS production may be a marker of β-cell resilience, highlighting differences in how β-cells respond to stress. Understanding this mechanism could offer new insights into why some β-cells are more vulnerable in T1D and potentially point to novel strategies for preserving β-cell function in diabetes. While our investigation into IFN-α signaling revealed how immune cytokines influence β-cell physiology, we also sought to explore immune landscape changes during disease progression. Using the Akoya Phenocycler, we mapped immune cell populations in the pancreata of human and diabetic mouse models and corresponding controls, providing insight into disease-associated immune changes.