The delivery of luminal substances across small intestinal epithelium via goblet cell associated antigen passages is increased in the presence of dietary gliadin.

Abstract

Abstract Celiac disease is an enteropathy caused by CD4+ T cell responses to dietary gliadin, resulting in damage to the intestinal mucosa and malabsorption. How gliadin peptides cross the epithelium to interact with the immune system is unclear. We used an in vivo imaging approach on live mice and ex vivo assays on mouse and human intestinal explants to evaluate how gliadin traversed the intestinal epithelium. We observed that gliadin crossed the epithelial barrier of mice and humans via the recently described goblet cell associated antigen passages (GAPs), and moreover, gliadin increased the formation of GAPs. The induction of GAPs by gliadin was independent of acetylcholine signaling, the pathway inducing GAP formation in the steady state. Consistent with the increase in GAPs induced by gliadin, LP-DCs isolated from mice given luminal ovalbumin (Ova) concurrently with gliadin induced enhanced antigen specific T cell responses to Ova in ex vivo LP-DC T cell co-culture assays. In vivo Ova specific T cell responses in the MLN were enhanced in mice given Ova concurrent with gliadin. Gliadin did not increase the antigen presentation capacity of the LP-DCs when added to ex vivo cultures, indicating that increased luminal antigen delivery via GAPs mediates the enhanced antigen specific T cell responses to luminal Ova. In the absence of GC’s and GAPs gliadin did not enhance the delivery of luminal antigens to the LP-DCs and did not enhance T cell responses to luminal antigens. These studies identify that gliadin uses GAPs to cross the epithelial barrier, and that gliadin induces further GAP formation in a goblet cell intrinsic manner, thus facilitating the delivery of gliadin and other antigens to the immune system.