Most foods do not elicit an inflammatory response in the gut, but the mechanisms underlying oral tolerance are not entirely clear. Andrea Cerutti and his colleagues now report that MUC2, a glycosylated protein that is a major component of the mucous layer lining the gut, also regulates tolerance of dendritic cells (DCs) to oral antigens (Science doi:10.1126/science.1237910).

The authors showed that MUC2 dampens the production of inflammatory cytokines by DCs exposed to bacteria. Moreover, MUC2 induced increased expression of IL-10 and other immunosuppressive factors and enhanced regulatory T cell development in vitro. Compared with wild-type mice, Muc2-deficient mice had more proinflammatory T cell subsets in their small intestine lamina propria (SI-LP), higher production of proinflammatory cytokines from SI-LP DCs and lower levels of immunosuppressive cytokines from DCs and intestinal epithelial cells. Muc2-deficient mice showed higher antibody and T cell responses to antigens delivered orally compared with wild-type mice, but these immune responses could be reduced by coadministration of MUC2 and antigen.

Credit: SPL / Science Source

The researchers then showed that glycosylated Muc2 interacts with DC surface galectin-3 and forms a complex with dectin-1 and the immunosuppressive receptor FcγRIIb. This interaction is required for the suppression of proinflammatory cytokine production by MUC2. These findings extend our understanding of the multifunctional role of MUC2 in the gut and the mechanisms regulating oral tolerance to ingested antigens.