Immune therapies that target beta-cell antigen-specific T cells are needed to prevent type 1 diabetes. T-cell exhaustion is a state of cellular dysfunction with decreased cytokine production, effector function and self-renewal capacity.Understanding T-cell exhaustion is an emerging area of research in chronic infection, cancer immunotherapy, and more recently, autoimmunity. While deleterious in the context of cancer, T-cell exhaustion would be desirable in autoimmune diseases like type 1 diabetes. High and persistent antigen exposure is important driver of T-cell exhaustion. However, despite chronic exposure to beta cell antigen, T cells go on to destroy beta cells in type 1 diabetes indicating retain cytotoxic function and self-renewal capacity of the T cells.
To understand this paradox, we have generated powerful animal models to test methods to induce T-cell exhaustion to prevent type 1 diabetes. We will study the number, function and exhausted phenotype of beta cell specific T cells in transgenic mice and their capacity to induce diabetes. We will also gain detailed mechanistic insight at the single cell level using transcriptomic profiling of islet reactive T cells. Our studies will lay the groundwork for developing future clinical studies.