Mucosal tolerance towards dietary antigens and intestinal microbiota is essential to maintain intestinal homeostasis, the breakdown of which results in development of inflammatory bowel disease. How luminal antigens are acquired by the immune system in a manner capable of inducing adaptive immunity, and the role of luminal antigen acquisition pathways in oral tolerance induction and maintenance is unknown. Recently, we identified a new pathway of luminal antigen delivery to dendritic cells in the lamina propria, which was mediated by goblet cells (GC) associated antigen passages (GAPs). The importance of GCs and mucus in barrier maintenance is well known, however the role of GCs and GAPs in tolerance induction and maintenance, and the events downstream of antigen delivery by GAPs to LP-DCs are unexplored.Methods:
Tolerogenic responses to dietary antigen, ovalbumin (Ova) were studied in mice where GCs were deleted, or when GAPs are inhibited but GCs remain and compared to corresponding control mice. In addition, detailed analysis of DCs and T cell subsets within the lamina propria (LP) was performed upon deletion of intestinal GCs.Results:
We observed that when GCs are deleted, or when formation of GAPs was inhibited, LP-DCs do not acquire luminal antigen in a manner capable of inducing adaptive immunity and antigen specific T cell responses in the MLN to luminal antigens is abrogated. Further oral tolerance failed to be established in the absence of GCs. Moreover, upon deletion of GCs, LP-DCs lose retinaldehyde dehydrogenase activity, the enzyme required for the production of all-trans retinoic acid, which induces T cells to become Tregs and express the integrin a4b7, which is necessary to home to the intestine. In addition, loss of GCs resulted in a rapid loss of Tregs in the small intestine LP, indicating that GCs also play a crucial role in the maintenance of intestinal Treg populations.Conclusions:
Hence, our results demonstrate that GCs and GAPs play a crucial role in the induction of oral tolerance and that GCs loss results in alterations of intestinal DC populations and loss of Tregs, indicating that GCs and GAPs have previously unappreciated roles in intestinal immune homeostasis.