Duodenal Influence on Endocrine Pancreatic Immunity: A Dominant Role for Shared Lymph Node Tonality

While it is appreciated that the continual exposure of the intestinal immune system to dietary content, commensal bacteria, and infections can have wide ranging effects on systemic immunity, the mechanism by which distal organs are affected is unclear. Here, I examined the unique effect of common lymph node (LN) drainage between a peripheral organ and the gut on imparting the effects of intestinal modulation to other sites. One organ in particular, the pancreas, shares several immunosuppressive LNs with the upper small intestine, the duodenum. How these tolerogenic pancreatic-duodenal LNs may impact pancreatic disease, such as protection from type I diabetes or pancreatic cancer, respectively, is unknown. I focused on these common LNs in the context of type I diabetes (T1D), as studies in human have linked enteric infection with diabetes onset. Using sequencing-based methods, I systematically characterized migratory dendritic cell (DC) gene expression profiles in the pancreas, liver and duodenum and the shared lymph nodes. These results revealed that while migratory DCs express distinct tissue specific signatures when present in their respective tissue, once in the shared LNs, these DCs become much more homogenous, expressing only remnants of the tissue of origin signature. In parallel, experiments utilizing pancreas-specific T cells demonstrated that upon duodenal infection pancreas-specific CD8+ T cells within these LNs became activated despite an uninfected pancreas, suggesting the fate of autoreactive T cells can be altered by intestinal modulation. Taken together, these results support the idea that the local LN milieu shapes the immune response to any antigen that enters the LN. These data may give mechanistic insight into links between enteric infection and T1D and provide a basis for targeting the pancreatic immune system via manipulation of the duodenal LN milieu. In addition, I generated a number of novel tools for further elucidation of the effects of shared LNs on pancreatic and duodenal immunity.