Autoreactive T cells destroy the pancreatic islets of Langerhans mediating the disease insulin dependent diabetes mellitus (IDDM). The ability of self-reactive T cells to destroy their targets is regulated by networks of cytokines that modulate the activation of these destructive autoimmune T cells. The NOD mouse is an important model of IDDM in humans, succumbing to disease through the participation of CD4 and CD8 T cells as well as antigen presenting cells. While the regulation of CD4 T cells is well characterized, the regulation of CD8 T is cell not fully understood. The overall goal of this project is to further our understanding of the regulation of CD8 T cells in the loss of immunological tolerance to pancreatic islets. Two complementary aims are proposed in this component. In the first aim we test the hypothesis that the functional specificity determining CD8 T cell cytolytic potential is opposite to that of CD4 T cells: type 2 cytokine responses being inductive of disease and type 1 responses being protective. This hypothesis will be tested utilizing NOD based transgenic mouse models where individual cytokines are expressed. The requirements for CD8 pathogenicity within these microenvironments will be determined in the studies proposed. In the second aim we will define the potential role of CD8 T cell tolerance in prevention of disease by DNA vaccination with the islet autoantigen GAD.
In specific aim #2 we will test the hypothesis that prevention of disease by GAD DNA vaccination is mediated through CD8 T cell tolerance to this islet antigen. In the experiments proposed we will determine the mechanisms of tolerance following DNA vaccination with the islet antigen GAD. We believe that the experiments in this project will increase our understanding of the regulation of CD8 T cells And further the prospect of DNA vaccination as a therapy for IDDM in humans.
