Autoimmune Stem-like CD8 T cells in Type 1 Diabetes

PROJECT SUMMARY T cell–mediated autoimmune diseases result from the breakdown of tolerance mechanisms in self-reactive CD8 T cells. However, many aspects of autoimmune CD8 T cell differentiation remain enigmatic, including where and how autoimmune T cell populations arise and are maintained and what molecular programs define autoimmune T cell states. Type I diabetes (T1D) is a CD8 T cell–mediated autoimmune disease; T1D pathogenesis is complex and involves immune infiltration of the pancreas and destruction of insulin-producing β cells by CD8 T cells. The non-obese diabetic (NOD) mouse model is a clinically relevant model of T1D, which shares many features with human disease. Utilizing the NOD model, we investigate autoimmune β cell-specific CD8 T cells differentiation state dynamics over the course of T1D. We identified a stem-like progenitor CD8 T cell population in the pancreatic lymph node that self-renews and gives rise to differentiated progeny, which migrate to the pancreas and destroy β cells. The goal of this application is to generate a deep mechanistic understanding of the niche- dependent intercellular interactions and signals in the pancreatic lymph node that maintain the autoimmune stem-like progenitor T cell pool and regulate differentiation, and to use this knowledge to develop strategies for therapeutic interventions. We will (i) employ innovative imaging and sequencing approaches to identify the spatial organization of pancreatic lymph node niches that determine diabetogenic T cell responses, (ii) determine the functional roles of key transcription factors controlling autoimmune T cell differentiation and test whether deletion or enforced expression of these transcription factors can alter autoimmune T cell states, and (iii) investigate autoimmune β cell-specific CD8 T cell states in human pancreatic lymph nodes and pancreas from organ donors with T1D. If successful, the proposed studies will provide important insights into autoimmune β cell-specific CD8 T cell programming in mouse and human T1D and could yield promising molecular and cellular targets for the prevention or treatment of T1D and other T cell-mediated autoimmune diseases.