Diabetes and other autoimmune endocrine diseases
Type 1 Diabetes is a disease caused by immune mediated destruction of beta cell mass, resulting in the loss of glycemic control. Following disease onset, subjects with Type 1 Diabetes exhibit diverse amounts of residual c-peptide, indicating varying levels of endogenous insulin production and beta cell function. Persistence of residual c-peptide is correlated with improved glycemic control and reduced risk of complications and its preservation has been used as a clinical endpoint in clinical trials. However, the immunologic factors that differentiate subjects who maintain measurable levels of c-peptide (slow progressors) from those whose levels continue to decline (rapid progressors) are not well characterized. Given their established relevance, we characterized the number, phenotype and transcriptional profiles of beta cell specific CD8+ T-cells in a cohort of subjects, stratified into slow progressors (those with c-peptide > 0.1ng/ml) and rapid progressors (those with undetectable c-peptide). Using a pool of tetramers corresponding to established HLA-A2 epitopes, we enumerated beta cell specific CD8+ T-cells in peripheral blood and sorted a portion of these cells for characterization by single cell RNA-Seq. Differential gene expression between slow and rapid progressors indicated differences in effector, exhaustion, and regulatory pathways. Assembly of autoantigen specific CD8 TCRs allowed analysis of diversity, revealing differences in clonal expansion between rapid and slow progressors. Cumulatively, our analysis uncovered aspects of T cell function and repertoire that correlate with disease progression.