Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing islet cells are targeted and destroyed by the immune system, especially by T cells. The events that lead to immune recognition of islet proteins in people genetically predisposed to autoimmunity are poorly understood. Many of the environmental triggers associated with T1D including viral infection, exposure to chemicals or free radicals, and dynamic glucose sensing, however, cause cellular stress within islets. In addition, the natural function of islet cells (to produce and release insulin) makes these cells especially susceptible to stress. The cells respond to stress by activating a program that protects them from death, but this results in mishandling of proteins leading to changes in there normal structure. In healthy individuals, this mishandling of proteins is not a problem; however, in individuals prone to autoimmunity, these proteins and the cells that make them may be targeted by the immune system. We hypothesize that the environmentally related events leading to this cellular stress in islet cells causes abnormal modification of proteins which in genetically predisposed patients, leads to abnormal immune system targeting causing the destruction of the islets. We have tested this hypothesis using a model system of T cell recognition of islets, in particular an islet protein called chromogranin A (CHgA) in a well established mouse model of T1D, demonstrating that T cells respond much more strongly to islets exposed to environmental triggers of cellular stress. These data support the hypothesis that cellular stress changes the proteins in the islet, and these changes facilitate the recognition of islets by T cells. We are now proposing to translate these findings further using human islet-reactive T cells, human islets and a humanized mouse model of T1D. The overarching goal of these studies is to determine in the humanized T1D animal model if the same modifications are demonstrated under conditions of cellular stress, and to determine how these modifications lead to the recognition of islets by the immune system. These studies are important because understanding how islet proteins come to be recognized by T cells will reveal targets for therapeutic intervention to prevent incorrect modification of islet proteins, protect islets from the immune system, and ultimately prevent T1D.