Microbial Sensing by Goblet Cells Controls Immune Surveillance of Luminal Antigens in the Colon

The delivery of luminal substances across the intestinal epithelium to the immune system is a critical event in immune surveillance resulting in tolerance to dietary antigens and immunity to pathogens. How this process is regulated is largely unknown. Recently goblet cell associated passages (GAPs) were identified as a pathway delivering luminal antigens to underlying lamina propria (LP) dendritic cells (DCs) in the steady state. Here we demonstrate that goblet cells (GCs) form GAPs in response to acetycholine (ACh) acting on muscarinic acetylcholine receptor (mAChR) 4. GAP formation in the small intestine (SI) was regulated at the level of ACh production, as GCs rapidly formed GAPs in response to ACh analogues. In contrast, colonic GAP formation was regulated at the level of GC responsiveness to ACh. Myd88 dependent microbial sensing by colonic GCs inhibited the ability of colonic GCs to respond to Ach to form GAPs and deliver luminal antigens to colonic LP-antigen presenting cells (APCs). Disruption of GC microbial sensing opened colonic GAPs and resulted in recruitment of neutrophils and APCs and production of inflammatory cytokines. Thus GC intrinsic sensing of the microbiota plays a critical role regulating the exposure of the colonic immune system to luminal substances.