University of Chicago
Duodenal control of pancreatic immunity via shared lymphatic drainage
We are interested in understanding how immune homeostasis is maintained in the digestive system, and how its failure can lead to allergies, chronic inflammation, autoimmunity or cancer. One way of striking the balance between immunosuppression and inflammation is by segregating these immune outcomes into separate gut lymph nodes (gLNs) with distinct immunological and metabolic properties. We aim to understand the mechanisms driving these compartmental differences and their global consequences in health and disease. Our current research focuses on three aspects:
- The role of the intestinal lymphatics in host immunity-microbe/food interaction. We hypothesize that the intestinal lymphatics and the lymph they carry actively contribute to shaping distinct gLN milieus. The lymphatics of the small intestine have the unique role of dietary lipid and hydrophobic molecule uptake, including microbial products. Lymphatic vessels respond and contribute to lymph composition and intestinal infections. Exploring how acellular lymph and site specific lymphatic remodeling upon intestinal insults shape immune niches is a novel avenue of interrogating how gut-luminal events influence local and systemic immunity.
- 2. LN macrophages (macs) as gut signal integrators. We postulate that gLN macs are gut compartment-specific environmental sensors, and respond by instructing innate and adaptive cells in the gLNs under physiological and inflammatory conditions. LN macs contain infections, take up antigens, and instruct dendritic cells (DCs) or B cells to orchestrate adaptive immunity. Most LN macs sit right at the lymph entry and exit site, at the anatomical and conceptual interface between incoming lymph and LN immune cells. We seek a fundamental molecular understanding of these so far poorly characterized LN macs, their role in setting distinct gLN milieus, and their suitability for immune modulation.
- 3. Duodenal control of pancreatic immunity. We hypothesize that the pancreatic-duodenal LNs represent unique sites of inter-organ immune crosstalk. We know these LNs are the most tolerogenic amongst the gLNs. We are investigating how pancreatic antigens and infections are perceived by its LNs, and how duodenal or pancreatic perturbation can alter immunity in the co-drained organ. Additionally, the duodenum may be the source of the pancreatic microbiome through the common bile duct, and first pass efferent blood from the gut a way of influencing pancreatic tissue-resident immune cells, providing two further routes by which the intestine could directly influence the immune system of the pancreas. Our findings may help explain the effect of enteric infection on T1D and the aggressive nature of pancreatic cancer, and provide a basis for targeting the pancreatic diseases via duodenal manipulation.