Antigen Specific T Cell Phenotypes Distinguishes Type 1 Diabetes Patients with High or Low Residual C-peptide

Type 1 Diabetes is caused by immune mediated destruction of beta cells, leading to dependence on exogenous insulin. After disease onset, subjects with diabetes exhibit diverse levels of residual beta cell function. Persistence of residual c-peptide correlates with improved glycemic control and its preservation has been used as a clinical endpoint. However, the immunologic factors that differentiate subjects who maintain measurable c-peptide (slow progressors) from those do not (rapid progressors) are not well understood. To define immunologic factors that differentiate slow and rapid progressors, we recruited a cohort of subjects with diabetes that included slow progressors (c-peptide > 0.1ng/ml) and rapid progressors (undetectable c-peptide) who had known HLA class I genotypes. We then utilized HLA class I tetramers to enumerate and characterize beta cell specific CD8+ T cells and sorted these cells to perform single cell transcript analysis and to assemble T cell receptor (TCR) sequences. Notably, we observed differences in epitope diversity between slow and rapid progressors. Single cell RNA-Seq revealed clear patterns of differential gene expression between slow and rapid progressors indicating differences in effector, exhaustion, and regulatory pathways. Analysis of autoantigen specific CD8 TCRs suggested differences in clonal expansion between rapid and slow progressors and revealed identical TCRs within different cell states. Cumulatively, this work revealed specific immunologic factors that differentiate subjects who maintain measurable levels of c-peptide from those whose levels continue to decline. These aspects of T cell function and repertoire that correlate with disease progression provide important insights that will drive further studies.