Intestinal Goblet cells and Goblet Cell Associated Antigen Passages regulate the balance between Tregs and Th17

Abstract

Abstract Tolerance towards dietary antigens and luminal microbes is essential to maintain homeostasis, the breakdown of which results in development of inflammatory bowel disease (IBD). T-helper 17 (Th17) and T-regulatory (Treg) cells are abundant in the intestinal mucosa, where they function to protect the host from pathogens and to restrain excessive effector T-cell responses, respectively. How the balance and switch between Treg and Th17 responses is maintained in the steady state to promote tolerance and how this balance becomes altered to favor Th17 responses in the setting of IBD is not known. We have identified that intestinal goblet cell (GC) associated antigen passages (GAPs), are a major pathway for steady-state luminal antigen transfer to lamina propria - dendritic cells (LP-DCs). In addition, GAPs are necessary for the imprinting of LP-DCs with tolerogenic properties, for the de novo induction of Tregs specific for dietary antigens, and the maintenance of pre-existing LP Tregs. Moreover, GAP inhibition results in the expansion of Th17 cells in the small intestine LP. Consistent with this, single cell profiling of intestinal lymphocytes revealed enhanced Th17 pathway gene signatures in mice lacking GCs. These observations strongly support that GCs/GAPs have a previously unappreciated role in maintaining the functional balance between Treg and Th17 cell.