Immune crosstalk through shared LN drainage in the digestive system

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PROJECT SUMMARY/ABSTRACT Hypothesis: Diseases of the pancreas are life-threatening, including pancreatic cancer (PDAC), affecting exocrine cells, and autoimmune diabetes (T1D), destroying insulin-producing β cells. External factors like infections and diet are implicated as triggers, but the disease origins remain elusive and cures are lacking. The immune system strongly contributes to disease progression, but what governs pancreatic adaptive immune tone is understudied, preventing effective immune-targeting therapy. Lymph nodes (LNs) are key sites for the initiation of tissue specific adaptive immunity, and here we hypothesize that LN sharing between pancreas and duodenum and liver influences the nature of pancreatic immunity. We postulate that both, the major lymph output from these co-drained organs and their more direct exposure to environmental perturbation, allow them to dictate LN environments, thus impacting pancreatic adaptive immune cell fate both during homeostasis and upon intestinal or hepatic insults. Finally, we propose that migratory dendritic cells (DCs) presenting pancreatic antigen are the key cellular target for such immune cross talk. This hypothesis will be tested in our Specific Aims (SA): SA #1 will characterize the phenotype of pancreatic antigen loaded DC and consequences for exocrine or endocrine pancreas specific T cell polarization in the co-drained LNs during homeostasis. SA #2 will test to what extent LN DCs and T cell fates change upon intestinal versus hepatic perturbation such as infections. SA #3 will assess the relative importance of sharing LNs with liver versus gut for the T cell landscape back in the exocrine and endocrine pancreatic tissue and, as a proof of principle, will investigate how duodenal infection, through LN sharing, affects pancreatic tissue T cells and the progression of T1D. Unique approach: 1. We will identify LN DCs loaded with pancreatic antigen by virtue of tracking tissue specific antigen biotinylation or fluorescent protein uptake. 2. We have generated novel mice that permit expression of the model antigen OVA from exocrine or endocrine pancreas, liver or gut, allowing for monitoring OVA specific T cell fate. This method permits the systematic comparison of tissue-specific T cell responses in the LNs shared with the liver versus the duodenum. Impact: This project will provide fundamental insights into how pancreatic immunity may be shaped by environmental fluctuations. While potential sources of pancreatic perturbation through LN sharing, liver and duodenum could turn out as anatomical routes for therapeutic intervention in the pancreas. Mechanistically the research will increase our understanding of DC imprinting in tissue versus LN and the impact of this “plasticity” on dictating T cell responses. More broadly, the proposal features LN sharing between organs as a previously unrecognized force shaping tissue specific immunity.