Genetics and Epigenetics of Type 1 Diabetes Self-Reactive T Cells.

Type 1 diabetes (T1D) serves as an exemplar of chronic autoimmune disease characterized by insulin deficiency due to pancreatic ß-cell destruction, leading to hyperglycemia and progressive organ failure. Until recently, therapeutic efforts to mitigate the root cause of disease have been limited by the challenges in studying mechanisms involved in immune tolerance in humans. The current clinical advances, and existing challenges, highlight a need to incorporate new insights into mechanisms into correlative studies that assess immune tolerance in the setting of delayed ß-cell destruction. Among several factors known to promote T1D, autoreactive T cells play a critical role in initiating and sustaining disease through their direct recognition and destruction of ß cells. Emerging research defining the genetic and epigenetic etiology of long-lived ß-cell-specific T cells is providing new insight into mechanisms that promote lifelong disease and future opportunities for targeted therapeutic intervention. This article will provide an overview of recent progress toward understanding the development of autoreactive T cells and epigenetic mechanisms stabilizing their developmental state during T1D pathogenesis.

Conserved epigenetic hallmarks of T cell aging during immunity and malignancy.

Chronological aging correlates with epigenetic modifications at specific loci, calibrated to species lifespan. Such 'epigenetic clocks' appear conserved among mammals, but whether they are cell autonomous and restricted by maximal organismal lifespan remains unknown. We used a multilifetime murine model of repeat vaccination and memory T cell transplantation to test whether epigenetic aging tracks with cellular replication and if such clocks continue 'counting' beyond species lifespan. Here we found that memory T cell epigenetic clocks tick independently of host age and continue through four lifetimes. Instead of recording chronological time, T cells recorded proliferative experience through modification of cell cycle regulatory genes. Applying this epigenetic profile across a range of human T cell contexts, we found that naive T cells appeared 'young' regardless of organism age, while in pediatric patients, T cell acute lymphoblastic leukemia appeared to have epigenetically aged for up to 200 years. Thus, T cell epigenetic clocks measure replicative history and can continue to accumulate well-beyond organismal lifespan.