Mucin glycans as novel immunoregulators of host response

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This project investigates the molecular mechanisms underlying a novel role of mucins as immunoregulators of gut homeostasis. Mucins are heavily glycosylated proteins covering the gastrointestinal epithelium, providing a physical and biological barrier function against harmful molecules while maintaining a homeostatic relationship with our gut microbiota. In addition to this protective function, secreted mucins were recently shown to implement a biological signaling to suppress excessive host immune response whereby mucins bind to dendritic cells (DCs), a key regulator for the gut immune system, thus inhibiting cellular activation. This immunosuppressive effect was proposed to be mediated in vivo by two carbohydrate-binding proteins, Galectin-3 and/or Dectin-1, expressed on DCs, although direct evidence of binding remains to be determined. This project addresses the specificity and implication of mucin glycan-DC interactions at the molecular level by combining expertise from the Juge’s Lab in gut mucin biology and Kawasaki’s Lab in gut immunology, both having common interest and complementary expertise in carbohydrate-lectin interactions. We will characterize mucin-lectin interaction at the molecular level using atomic force microscopy and reporter cell-based assays and determine the immune response of human or mouse DCs in response to mucin treatment. Several outputs such as cytokine production and proliferation will be assessed by ELISA and flow cytometry. We will then investigate the carbohydrate structures on mucins responsible for the reported immunosuppressive effect by using mucins of different glycosylation signatures following a chemo-enzymatic approach. Since mucin glycosylation is altered in inflammation and cancer, defining the precise mucin glycan structures recognised by mammalian lectins to elicit a tolerogenic response is critical to understand the role of these interactions in health and disease.

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