Immune crosstalk via shared lymph nodes in the upper digestive system influences pancreatic adaptive immunity and alters disease progression 2302

Abstract Description Lymph nodes (LNs) are strategically positioned to achieve site-specific adaptive immunity. In the upper digestive system, however, LNs are shared by distinct organs – liver, pancreas and duodenum. We previously showed that intestinal infections can alter β-cell-reactive T cell fate via this co-drainage. To explore the immune modulatory role of this shared anatomy beyond β-cell immunity, we created three mouse lines expressing OVA as a self-antigen upon tissue-specific Cre recombination, with distinct subcellular locations (secretory, cytosolic or transmembrane). Using OT-I/II T cell transfers, we found that both tissue properties and antigen location dictated immune visibility. Cytosolic OVA in the liver and pancreas, but not the gut, needed apoptosis-inducing agents to elicit T cell proliferation in LNs, while other OVA forms triggered T cell responses at homeostasis. Intestinal viral infection increased liver- and exocrine-pancreas-specific TH1 cells and cytotoxic lymphocytes, while liver perturbation led to more pancreas- and gut-specific TH1 cells at the expense of Treg in co-drained LNs. Pancreas-reactive cytotoxic T cells infiltrated the tissue, causing autoimmune tissue destruction but improved tumor control. The study offers a tool for investigating self-reactivity in cell types with specific Cre drivers and highlights the extensiveness of the immune crosstalk in the upper digestive system via LN sharing, with implications for pancreatic and hepatic disease modulation. Funding Sources Supported by NIH R01 DK133393 Topic Categories Mucosal and Regional Immunology (MUC)