Factors that determine islet antigen-specific T cell expansion before the onset of Type 1 diabetes

Summary Our goal is to prevent the cytotoxic CD8+ T cell-mediated destruction of insulin-producing pancreatic beta cells that leads to type 1 diabetes. Islet-specific CD8+ T cells appear in cycles in the blood reflecting waves of clonal proliferation, they expand just before diagnosis of diabetes and their quantity in the islets reflects the extent of pathology.

Project Details

Our goal is to prevent the cytotoxic CD8+ T cell-mediated destruction of insulin-producing pancreatic beta cells that leads to type 1 diabetes. Islet-specific CD8+ T cells appear in cycles in the blood reflecting waves of clonal proliferation, they expand just before diagnosis of diabetes and their quantity in the islets reflects the extent of pathology. These data are consistent with progression to diabetes being determined by islet-specific T cell number. However, how T-cell proliferation is regulated during spontaneous progression to type 1 diabetes is poorly understood. Insight into this and the ability to measure it, or the factors that regulate it, would provide valuable prognostic information in individuals at risk of developing type 1 diabetes.

We have recently observed that islet-specific CD8+ T cells are dramatically increased in number in interferon- receptor mutant NOD mice. This explains why diabetes occurs in these mice in which other hallmarks of type 1 diabetes are suppressed and is a strong indication that the number of CD8+ T cells may be an informative marker of disease progression.

Our hypothesis is that antigen-specific CD8+ T cell expansion determines the rate of progression of diabetes and that this expansion is associated with a change in T-cell phenotype and increased cytotoxic function. We aim to identify mechanisms that regulate proliferation of antigen-specific CD8+ T cells.