Sex-dependent roles of the IFIH1 risk variant in type 1 diabetes pathogenesis

The common single nucleotide polymorphism within the anti-viral cytosolic RNA sensor IFIH1 (rs1990760) results in an amino acid change (IFIH1^A946T; IFIH1^R) and has been associated with type I interferon (IFN I) dysregulation and multiple autoimmune diseases, including type 1 diabetes (T1D). We hypothesized that IFIH1^R would stimulate heightened inflammation leading to immune cell alterations and the promotion of T1D pathogenesis. To test this, we generated Ifih1^R knock-in mice on the non-obese diabetic (NOD) background (NOD.Ifih1^R). Our results revealed that NOD.Ifih1^R mice exhibited an enhanced ISG signature, indicative of increased IFN I signaling. Next, we investigated the impact of heightened inflammation on immune cells, showing that NOD.Ifih1^R mice displayed increased frequency of plasma cells as compared to non-risk Ifih1 (NOD.Ifih1^NR) mice. Further, frequency and activation of CD8⁺ T cells were altered in NOD.Ifih1^R mice in a tissue-dependent manner. Interestingly, female NOD.Ifih1^R mice exhibited a significant acceleration of diabetes compared to NOD.Ifih1^NR mice. Though this disease acceleration was not displayed by male NOD.Ifih1^R mice, insulitis was increased in male risk animals. Together, these results suggest immune cell activation is altered due to the inflammatory environment within the risk mice promoting diabetes pathogenesis. These findings advance our knowledge on the link between IFIH1^R and T1D.