Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing pancreatic β cells by immune cells, leading to insulin deficiency. T1D is driven by intricate interactions between the innate and adaptive immune mechanism, and autoreactive T-cells perpetuate destruction of islets cells following priming by proinflammatory cytokines and chemokines. Although the primary risk factor for T1D is genetic, environmental factors have been implicated as possible triggers or accelerators in the pathogenesis of T1D. Viral infections, especially enteroviruses have been implicated in the pathogenesis of T1D. Mechanisms proposed for such association include virus-induced innate immune responses including type I interferon (IFN) that unmask β-cells for recognition by autoreactive T-cells. Type I IFN has been implicated in the early stages of T1D autoimmunity and previous studies in our rat model highlight the essential role of virus-induced, type I IFN responses as rats lacking type I IFN signaling (Ifnar1-/- LEW.1WR1 rats) have delayed onset and up to 50% reduction in the incidence of autoimmune diabetes. The goal of my thesis research is to delineate type I IFN dependent and independent mechanisms that drive autoimmune diabetes using LEW.1WR1 rats, models in which autoimmune diabetes can be induced with combined poly I:C and virus infection. I hypothesize that in Ifnar1-/- LEW.1WR1 rats, type II IFN and non-interferon innate immune responses compensate for type I IFN responses and drive the adaptive immune cells to mediate autoimmune diabetes. Transcriptome profiles of wild type (WT) and Ifnar1-/- LEW.1WR1 rat islets over a time course were analyzed to define temporal transcriptional events that lead to autoimmune diabetes in prediabetic LEW.1WR1 rats following poly I:C and KRV treatment. Pancreatic sections of treated rats were also analyzed using RNA-in situ hybridization (RNA-ISH) to spatially map islet cells inflammation and to correlate with local islet T cell recruitment. In WT LEW.1WR1 rats, a transcriptional signature characterized by interferon-stimulated genes, chemokines, major histocompatibility class I, and genes for the ubiquitin-proteasome system was identified in subsets of β and α cells. These signature cells increased in frequency over time and correlated with local islet T cell recruitment. Type I IFN genes as well as genes for the ubiquitin-proteasome system are largely suppressed in poly I:C + KRV treated Ifnar1-/- rats compared to control Ifnar1-/- rats, while MHC class I genes were upregulated in poly I:C + KRV treated Ifnar1-/- rats compared to control Ifnar1-/- rats. Cytokine analysis reveal an increase in levels of IFNγ in poly I:C + KRV treated Ifnar1-/- rats compared to WT rats. Blocking IL-1R does not protect from diabetes in WT and Ifnar1-/- treated rats although both are protected with depletion of CD8+ T cells. Infiltration of immune cells in WT rats was accompanied with extensive islet damage while infiltration in Ifnar1-/- rats was less destructive. Inhibition of the JAK signaling pathway confirmed the requirement of the JAK-STAT signaling pathway and CD8+ T cells in progression to diabetes in the WT rats and further testing to confirm this requirement in Ifnar1-/- rats is ongoing. Although CCL proteins were expressed on immune cells, blockade of CCR5 had no effect on diabetes incidence. Collectively, the results from these studies provided mechanistic insights into the essential role of virus-induced, innate immune responses in the early phase of autoimmune diabetes pathogenesis.