In autoimmune diabetes the transition from benign to pernicious insulitis requires an islet cell response to tumor necrosis factor α

The islet-infiltrating and disease-causing leukocytes that are a hallmark of insulin-dependent diabetes mellitus produce and respond to a set of cytokine molecules. Of these, interleukin 1 beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma are perhaps the most important. However, as pleiotropic molecules, they can impact the path leading to beta cell apoptosis and diabetes at multiple points. To understand how these cytokines influence both the formative and effector phases of insulitis, it is critical to determine their effects on the assorted cell types comprising the lesion: the effector T cells, antigen-presenting cells, vascular endothelium, and target islet tissue. Here, we report using nonobese diabetic chimeric mice harboring islets deficient in specific cytokine receptors or cytokine-induced effector molecules to assess how these compartmentalized loss-of-function mutations alter the events leading to diabetes. We found that islets deficient in Fas, IFN-gamma receptor, or inducible nitric oxide synthase had normal diabetes development; however, the specific lack of TNF-alpha receptor 1 (p55) afforded islets a profound protection front disease by altering the ability of islet-reactive, CD4(+) T cells to establish insulitis and subsequently destroy islet beta cells. These results argue that islet cells play a TNF-alpha-dependent role in their own demise.