1Although lymphocyte infiltration and islet destruction are hallmarks of diabetes, the mechanisms of ␤-cell destruction are not fully understood. One issue that remains unresolved is whether cytokines play a direct role in ␤-cell death. We investigated whether ␤-cell cytokine signaling contributes to autoimmune type 1 diabetes. We demonstrated that NOD mice harboring

Coxsackievirus (CV) is an important human pathogen that has been linked to the development of autoimmunity. An intact pancreatic β cell IFN response is critical for islet cell survival and protection from type 1 diabetes following CV infection. In this study, we show that IFNs trigger an antiviral state in β cells by inducing the expression of proteins involved in intracellular antiviral defense. Specifically, we demonstrate that 2′,5′-oligoadenylate synthetases (2-5AS), RNase L, and dsRNA-dependent protein kinase (PKR) are expressed by pancreatic islet cells and that IFNs (IFN-α and IFN-γ) increase the expression of 2-5AS and PKR, but not RNase L. Moreover, our in vitro studies uncovered that these pathways play important roles in providing unique and complementary antiviral activities that critically regulate the outcome of CV infection. The 2-5AS/RNase L pathway was critical for IFN-α-mediated islet cell resistance from CV serotype B4 (CVB4) infection and replication, whereas an intact PKR pathway was required for efficient IFN-γ-mediated repression of CVB4 infection and replication. Finally, we show that the 2-5AS/RNase L and the PKR pathways play important roles for host survival during a challenge with CVB4. In conclusion, this study has dissected the pathways used by distinct antiviral signals and linked their expression to defense against CVB4.