Novel role of intestinal Goblet cells and Goblet Cell Associated Antigen Passages in induction of tolerance to dietary antigens and promoting intestinal homeostasis

Abstract

Abstract Mucosal tolerance towards luminal antigens is a process fundamental to intestinal homeostasis, the breakdown of which results in onset of inflammatory bowel disease. How luminal antigens cross the intestinal epithelium to interact with the immune system in a manner capable of induction and maintenance of oral tolerance is unknown. We have identified a new pathway of luminal antigen delivery to dendritic cells (DC) in the lamina propria (LP), which was mediated by goblet cells (GC) associated antigen passages (GAPs). The role of GCs and GAPs in promoting mucosal tolerance is unexplored. We studied tolerogenic responses to dietary antigen, ovalbumin (Ova) in mice where GCs were deleted, or when GAPs are inhibited but GCs remain and compared to corresponding control mice. In the absence of GCs or functional GAPs, LP-DCs could not acquire luminal antigens in a manner capable of inducing antigen specific T cell responses in the draining mesenteric lymph nodes (MLN). Moreover, deletion of GCs/GAPs resulted in loss of induction of regulatory T cells in the MLN and abrogated tolerance to dietary antigens. In addition, loss of GCs/GAPs resulted in rapid reduction of pre-existing induced Treg population in the SI-LP. Notably, the in absence of GCs/GAPs resulted in rapid expansion of IL-17 producing T cells in the small intestine, indicating that GCs and GAPs play a crucial role in balancing the Treg/Th-17 axis in the intestine. Hence, suggesting that GCs and GAPs play a crucial role in the induction and maintenance of oral tolerance. These findings identify a previously unappreciated role of GCs in maintaining the Treg/Th17 balance and that processes resulting in inadequate formation of GAPs may underlie the loss of tolerance to luminal antigens.