Type I IFN–Driven Immune Cell Dysregulation in Rat Autoimmune Diabetes

Abstract

Type 1 diabetes is a chronic autoimmune disease, characterized by the immune-mediated destruction of insulin-producing β cells of pancreatic islets. Essential components of the innate immune antiviral response, including type I IFN and IFN receptor (IFNAR)-mediated signaling pathways, likely contribute to human type 1 diabetes susceptibility. We previously showed that LEW.1WR1 <i>Ifnar1</i> ^-/- rats have a significant reduction in diabetes frequency following Kilham rat virus (KRV) infection. To delineate the impact of IFNAR loss on immune cell populations in KRV-induced diabetes, we performed flow cytometric analysis in spleens from LEW.1WR1 wild-type (WT) and <i>Ifnar1</i> ^-/- rats after viral infection but before the onset of insulitis and diabetes. We found a relative decrease in CD8⁺ T cells and NK cells in KRV-infected LEW.1WR1 <i>Ifnar1</i> ^-/- rats compared with KRV-infected WT rats; splenic regulatory T cells were diminished in WT but not <i>Ifnar1</i> ^-/- rats. In contrast, splenic neutrophils were increased in KRV-infected <i>Ifnar1</i> ^-/- rats compared with KRV-infected WT rats. Transcriptional analysis of splenic cells from KRV-infected rats confirmed a reduction in IFN-stimulated genes in <i>Ifnar1</i> ^-/- compared with WT rats and revealed an increase in transcripts related to neutrophil chemotaxis and MHC class II. Single-cell RNA sequencing confirmed that MHC class II transcripts are increased in monocytes and macrophages and that numerous types of splenic cells harbor KRV. Collectively, these findings identify dynamic shifts in innate and adaptive immune cells following IFNAR disruption in a rat model of autoimmune diabetes, providing insights toward the role of type I IFNs in autoimmunity.