Investigating Tissue-Specific Immunity in the Upper Digestive System

The immune system must balance effective responses against pathogens and malignancies with tolerance towards self. The digestive system, comprising the liver, pancreas and intestine, represents a uniquely interconnected organ system: tissue specific characteristics such as epithelial barriers, food exposure and commensal microbes may impact the nearby organs through shared lymphatic drainage, ductal systems and vasculature. Despite their close anatomical and developmental relationships, how these tissues coordinate innate and adaptative immune responses while maintaining tissue specific needs remains incompletely understood. This thesis investigates how antigen source, inflammatory context and inter-tissue communication collectively shape tissue-specific immunity across the gut-pancreas-liver axis. First, we examine how antigen source, dietary versus intestinal epithelial self-antigen, shapes CD4+ T cell fate in gut-draining lymph nodes (gLNs). Using oral Ovalbumin (OVA) administration and transgenic mice expressing epithelial OVA in distinct subcellular compartments, we demonstrate that RORγt⁺MHC-II⁺ antigen-presenting cells (APCs), while essential for tolerance induction to dietary antigens, are dispensable for tolerance to self-antigens. Furthermore, the subcellular localization of self-antigens differentially governs their access to specific APC subsets, with direct consequences for susceptibility to T-cell-mediated immunopathology. Secondly, leveraging these models in the context of shared lymphatic drainage, we define how the liver, pancreas and intestine employ distinct tolerance mechanisms—immunological ignorance, clonal deletion, or regulatory T (Treg) cell induction—at homeostasis. These outcomes are determined by both tissue origin and subcellular location of self-antigens. We further show that lymph node co-drainage selectively influences Treg cell differentiation without overriding tissue-intrinsic tolerance programs, and that inflammatory perturbations in one tissue can unmask pathogenic T cell responses in another co-drained organ. Finally, we investigate an additional axis of inter-organ immune communication between the pancreas and intestine by focusing on the REG/Reg gene family, a conserved group of antimicrobial and pancreatitis-associated proteins. We demonstrate that REG/Reg isoforms exhibit distinct baseline expression patterns and inducibility across tissues. A subset of REG/Reg members is inducible, microbiota-responsive, and IL-22-dependent, whereas other isoforms are constitutively expressed. Notably, intestinal perturbations selectively upregulate inducible Reg members in the pancreas, revealing coordinated regulation of innate immunity across organs. Collectively, this thesis identifies antigen origin, whether dietary versus self or self-derived from distinct cellular compartments, as a key determinants of T cell fate. These factors shape adaptive immune outcomes by directing access to specialized APC subsets and distinct tolerance pathways. In parallel, this work highlights inter-organ communication, mediated through both shared lymphatic drainage and microbiota-responsive signals that likely use the blood route as a mechanism for coordinating immune responses across the upper digestive system. Together, these findings add new layers to how tissue specific immune homeostasis and disease are defined, potentially explaining pathologies with hitherto unknown etiologies and offering novel therapeutic strategies for combatting autoimmune disorders and cancer.