Type 1 diabetes (T1D) serves as an exemplar of chronic autoimmune disease characterized by insulin deficiency due to pancreatic β-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 β-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 β cells. Emerging research defining the genetic and epigenetic etiology of long-lived β-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.
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