Defining the role of CD4 T cells in autoimmune CD8 T cell differentiation and function in type 1 diabetes

PROJECT SUMMARY Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease that results from the breakdown of tolerance mechanisms in self-reactive T cells, leading to immune infiltration of the pancreas and the destruction of insulin- producing b cells. Patients with T1D require lifelong exogenous insulin treatment and often develop multiorgan dysfunction, emphasizing the need for effective treatment strategies. β cell-specific CD8 T cells are the primary pathogenic population that eliminate insulin-producing b cells in the pancreatic islets, yet intriguingly, MHC class II haplotypes confer the greatest genetic risk for T1D development suggesting a critical role of CD4 T cells in disease initiation and progression. However, many aspects of autoimmune β cell-specific CD4 T cell differentiation and function remain enigmatic, including where and how autoimmune CD4 T cell populations arise and are maintained and their exact function in driving T1D. Our lab previously identified a stem-like CD8 T cell population which self-renews and gives rise to differentiated progenies which migrate to the pancreas and eliminate b cells; the stem-CD8 T cell pool is absolutely required for sustained b cell destruction. The goal of this application is to generate a deep understanding of the phenotypic and molecular features and functional role of β cell-specific CD4 T cell populations in driving T1D and specifically CD8 T cell stemness, differentiation and function. We will leverage the non-obese diabetic (NOD) mouse model, a clinically relevant model of T1D, which shares many features with human disease to (i) assess heterogeneity and polarization/differentiation states of CD4 T cells, (ii) determine the importance of key transcription factors in regulating CD4 T cell function, and (iii) employ innovative spatial sequencing technologies to identify cell-cell interactions and signals driving β cell destruction. Our proposed studies will provide important insights into autoimmune b cell-specific T cell programming and function which could yield novel therapeutic targets for the prevention or treatment of T1D and other T cell-mediated autoimmune diseases.