HLA class I overexpression within islets and the expansion of autoreactive CD8+ T cells are characteristic events during the pathogenesis of type 1 diabetes (T1D). We propose that CD8+ T cells display epigenetic markers, including CpG methylation, that are initiated during T cell activation and differentiation and persist in established disease. Further, we predict these marks foretell the transcriptional profile and effector phenotypes of these autoreactive effector populations. To address this hypothesis, we assessed the global methylation signature of CD8+ T cells isolated from tissues derived from individuals with T1D, multiple autoantibody positive at-risk subjects, and normal healthy controls. Preliminary analyses demonstrated variable DNA methylation patterns at a number of unique loci between patients with T1D and controls.
These data demonstrate our ability to isolate CD8+ T cells from the pancreatic-draining lymph nodes of nPOD subjects for epigenetic studies. Preliminary analyses suggest several distinct loci display differential methylation patterns in T1D, at-risk, and controls subjects. Ongoing studies are underway to validate targets deferentially methylated in additional nPOD and clincal PBMC samples, and subsequently assess their functional impact on CD8+ T cells in T1D.