Type 1 diabetes (T1D) is a chronic autoimmune disease targeting pancreatic beta cells. The incidence of T1D has been increasing, a trend inexplicable by genetic predisposition alone, indicating that environmental factors such as viruses play important roles in triggering the disease. Decades of research have provided epidemiological evidence for an association between T1D and enteroviruses, particularly coxsackieviruses. As shown in nPOD donors,T1Dis associated with higher rates of viral RNA, capsid protein, and associated immune markers compared to non–diabetic controls. However, there remains limited mechanistic evidence establishing how viral infections disrupt immune homeostasis to enable autoimmune destruction. Recent evidence demonstrates that pancreatic immune homeostasis depends on regulatory interactions between tissue–resident memory T cells and macrophages. We hypothesize that enterovirus infections convert protective tissue–resident macrophages to pathogenic phenotypes, disrupting regulatory networks that normally prevent autoimmune T cell activation against beta cells. We will examine archived pancreatic tissue sections from nPOD. We will compare non–diabetic donors and donors with T1D, specifically examining donors with or without detectable enterovirus infection (VP1+ vs VP1–) as identified by the nPOD–virus group. We will also exploit the organ donor pancreas slice platform, which is well established in our laboratory, as this is ideally suited to test this hypothesis in human pancreas tissue. Pancreatic tissue slices are thick sections of pancreas that enable functional analysis of live tissue in which the immune component in the pancreas is preserved and can be investigated; this includes tissue–resident macrophages and T cells. The study of pancreas slices enables the ability to investigate both functional and spatial interactions as the tissue architecture is preserved. Overall, this investigation will generate mechanistic insights into how enterovirus infection disrupts tissue–resident macrophage regulatory networks in human pancreatic tissue, establishing critical preliminary data linking viral triggers to the initiation of autoimmune diabetes. These findings will inform future comprehensive studies of therapeutic interventions targeting macrophage phenotypes and immune checkpoint pathways to preserve protective immune networks and prevent irreversible beta cell loss.
