Beta cell-specific CD8+ T cells maintain stem-cell memory-associated epigenetic programs during type 1 diabetes (WGBS)

The pool of beta cell-specific CD8+ T-cells in type 1 diabetes (T1D) sustains an autoreactive potential despite having access to a constant source of antigen. To investigate the long-lived nature of these cells, we established a DNA methylation-based T cell “multipotency index” and found that beta cell-specific CD8+ T-cells retained a stem-like epigenetic multipotency score. Single cell ATAC-seq analysis confirmed the co-existence of naive and effector-associated epigenetic programs in individual beta cell-specific CD8+ T-cells. Assessment of beta cell-specific CD8+ T-cell anatomical distribution and the establishment of stem-associated epigenetic programs revealed that self-reactive CD8+ T-cells isolated from murine lymphoid tissue retained developmentally plastic phenotypic and epigenetic profiles relative to the same cells isolated from the pancreas. Collectively, these data provide new insight into the longevity of beta cell-specific CD8+ T cell responses, and document the utility of this novel methylation-based multipotency index for investigating human and mouse CD8+ T-cell differentiation. Human naïve, TEM, TCM, and TSCM polyclonal CD8 T cells were sorted from healthy donors. Naive and Tetramer+ CD8 T cells were sorted from HIV HAART and T1D patients. whole-genome DNA methylation analysis was performed as previously described (Abdelsamed, et al. JEM 2017, PMID: 28490440). Naïve and NRP-V7 tetramer+ CD8 T cells were sorted from pancreatic islets, lymphnodes, and spleen of NOD mice. whole-genome DNA methylation analysis was performed as previously described (Ghoneim, et al. Cell 2017, PMID: 28648661). Single cell ATACseq was performed using the 10X Genomics platform per the manufacturers instructions.