SUMMARY This proposal leverages our group’s complementary expertise in tissue-on-a-chip technology, immunology, pluripotent cell derivation and differentiation, and islet biology to create robust systems containing human islet cells, immune cells, and other features to recapitulate the process of islet autoimmunity in type I diabetes (T1D). The UG3 phase of this proposal will improve upon already-robust microdevices and develop new cell lines and assays that will enable studies of autoimmunity in an isogenic setting. The UH3 phase of this proposal will exploit these tools and platforms to develop isogenic models that can be used to study immune-islet interactions. The focus of the UH3 phase will be to investigate the determinants of islet infiltration and killing, and to determine the effects of mutations in T1D-associated genes on this process. In addition, these in vitro systems will be used to pilot the use of cellular therapies to interrupt the autoimmune attack of islets. The specific aims of the UG3 phase are: Aim 1: To expand the biomimetic platform Aim 2: To develop models of T cell-mediated autoimmunity Aim 3: To establish new iPSC lines and novel reporters of b cell stress and death The specific aims of the UH3 phase are: Aim 1: To develop isogenic models of autoimmune T1D Aim 2: To identify determinants of islet infiltration and immune killing Aim 3: To perform genetic studies of autoimmunity in T1D