IntroductionInnate responses to viruses depend on pathogen recognition sensors that detect viral products and trigger the secretion of type I interferons (IFN-I), i.e., . Two types of sensors detect double-stranded (ds) RNA generated during infection with RNA viruses: endosomal TLR-3 and cytoplasmic retinoic acidinducible gene-I-like (RIG-I-like) receptors (RLR). TLR3 senses the dsRNAs that reach the endosomal compartment after phagocytosis of virally infected cells or apoptotic debris. RLRs include 2 IFNinducible helicases, melanoma differentiation-associated gene 5 (MDA5) and RIG-I, which detect dsRNA intermediates that are generated in the cytoplasm during viral replication. MDA5 specializes in the detection of picornaviruses, whereas RIG-I senses many other RNA viruses (5). These viral specificities depend on the ability of MDA5 and RIG-I to recognize dsRNA molecules of different lengths, structures, and 5′ caps (6-9).TLR3 transmits its intracellular signal through the adaptor protein Toll/IL-1 receptor domain-containing adaptor-inducing IFN-β (TRIF), which activates the transcription factor IFN regulatory factor-3 (IRF-3) and induces IFN-β production (1-4). RIG-I and MDA5 signal through another adaptor, IFN-β promoter stimulator-1 (IPS-1), which activates IRF-3 and IRF-7, inducing both IFN-β and IFN-α production. A third RLR, laboratory of genetics and physiology-2 (LGP2), detects dsRNA but lacks signaling domains and is thought to regulate MDA5 and RIG-I (10-12). IFN-I induces an antiviral state in uninfected cells and promote apoptosis of infected cells, limiting viral spread (13). Moreover, IFN-I has independent immunomodulatory effects and helps to orchestrate NK, T, and B cell responses, which facilitate viral clearance (13-15).Type I diabetes (T1D) is an autoimmune disease that is primarily caused by selective destruction of islet β cells of the endocrine pancreas by autoreactive T cells (16,17). Predisposing genetic factors, particularly MHC class II polymorphisms, play a predominant role in the pathogenesis of T1D. However, and experimental (23-25) studies have suggested that viral infections also may contribute to T1D, particularly infections by members of the enterovirus family of RNA viruses. These viruses may induce T1D by directly causing β cell damage and subsequent release of autoantigens that trigger autoreactive T cells (26)(27)(28)(29). Paradoxically, the host IFN-I response can have detrimental effects when it activates preexisting autoreactive T cells that escaped thymic selection (30-33). Accordingly, a synthetic analog of viral dsRNA, poly(I:C), precipitates diabetes in mouse and rat models, acting in part through . Consistent with this, genetic studies have recently shown that resistance to T1D is associated with polymorphisms in MDA5 that diminish the IFN-I response to dsRNA (41-44). Collectively, these studies pose a conundrum: by eliciting IFN-I response, dsRNA sensors may limit the cytopathic effect of β cell-tropic viruses, but they can also precipitate T1D by promoting IFN-I-ind...