Islet-specific CD8 T cells in the pathogenesis of type 1 diabetes

Project Summary Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the destruction of insulin-producing beta cells in the pancreas. CD8 T cells play a crucial role in this process, but the specific antigens they target and the molecular mechanisms driving their pathogenicity remain poorly understood. This knowledge gap hinders the development of targeted therapies to prevent or reverse T1D progression. Our proposed research aims to address this critical need by comprehensively investigating CD8 T cell antigen specificity and molecular signatures across different stages of T1D development. This project will employ innovative high-throughput screening methods, single-cell RNA sequencing, and advanced computational analyses to achieve three main objectives: (1) Identify novel epitopes recognized by islet-infiltrating CD8 T cells from T1D organ donors, focusing on both native proteins and potential neoepitopes, such as hybrid insulin peptides and RNA splice variants, preferentially expressed by ‘stressed’ islets. (2) Determine the molecular phenotypes specific to islet-reactive CD8 T cells within pancreatic lymph nodes of individuals at various stages of T1D development, comparing them to virus-specific T cells to elucidate unique features associated with autoimmunity. (3) Characterize the molecular signatures of preproinsulin-specific CD8 T cells in peripheral blood across different stages of T1D development, from prediabetic (islet autoantibody-positive) individuals to those with new-onset T1D. By integrating data from these complementary approaches, we expect to gain unprecedented insights into the antigen specificity and functional states of autoreactive CD8 T cells throughout T1D progression. This research has the potential to revolutionize our understanding of T1D pathogenesis and enable the development of novel biomarkers for early detection and monitoring of disease progression. Moreover, the identification of key molecular pathways involved in T cell activation and beta cell destruction may guide the design of more effective, targeted immunotherapies for T1D prevention and treatment. Ultimately, this project aims to improve the lives of individuals at risk for or living with T1D by identifying novel T cell epitopes and molecular signatures specific to disease progression. These findings will pave the way for developing more accurate predictive biomarkers and antigen-specific immunotherapies, bringing us closer to the goals of early intervention, disease prevention, and potential reversal of beta cell destruction in T1D.