Our understanding of type 1 diabetes (T1D) has been advanced greatly by studies carried out using mice and rats. However, rodents are not humans and progress in the understanding of the pathogenesis of T1D in humans has been impeded by the a lack of assays that permit the direct in vivo analysis of diabetogenic human T cell populations without putting individuals at risk. The availability of spleen, bone marrow, and thymus samples from T1D and islet autoantibody-positive donors provides an opportunity to analyze the diabetogenic function of these cell populations following engraftment in newly developed humanized mouse model systems. This work is based on our recently developed immunodeficient mice that express human HLA molecules and are optimized for human immune cell engraftment. Our goal is to use unique tissues available from nPOD to recapitulate autoimmune T1D in humanized mice. We will engraft human hematopoietic stem cells and immune cells into HLA-matched NSG mice and determine the ability of cells from T1D donors to attack islets and induce the destruction of insulin-producing cells. The knowledge obtained from these studies will permit us to elucidate the pathogenesis of T1D and to develop new approaches for preventing or curing the disease.