Viral infections have previously been implicated as a trigger of autoimmune diabetes. In this study, we compared a viral mimic with other microbial components derived from bacteria in triggering diabetes development in C57BL/6-rat insulin promoter-B7. 1 mice that do not normally develop diabetes. It is striking that only the viral mimic induced the development of diabetes in our model system. Further mechanistic studies suggest that diabetes is induced, in part, by the combination of direct recognition of this virus-like stimulus by pancreatic islets through the expression of the innate immune receptor, Toll-like receptor 3. In addition, the functions of APCs are up-regulated, and this could stimulate islet Ag-reactive T cells that will attack β cells leading to autoimmune diabetes.