Microbial sensing by goblet cells controls immune surveillance of luminal antigens in the colon

Abstract

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.

Airway epithelial SPDEF integrates goblet cell differentiation and pulmonary Th2 inflammation

“…Alternatively, goblet cells induced by SPDEF may have a direct role in enhancing innate immune responses. Recent findings that goblet cells provide conduits for transepithelial delivery of tolerogenic antigens from the intestinal lumen to CD103 + DCs provide a precedent for a role for goblet cells in communicating with DCs to influence innate immune responses in epithelia (42).…”

Reg4 + deep crypt secretory cells function as epithelial niche for Lgr5 + stem cells in colon

“…S4A). By GSEA analysis, we compared our data with gene signatures of Goblet cells in both SI and colon (24), Paneth cells, enteroendocrine cells (8), and stem cells in SI (25). Reg4 + cells from colonic crypts resembled Paneth cells, and were less related to Goblet cells from colon or SI, or to enteroendocrine cells (Fig.…”

“…The unbiased gene set enrichment analysis was performed with Gene Set Enrichment Analysis (software.broadinstitute.org/gsea/index.jsp). Preranked lists of mean expression changes and input signatures were derived from published microarray and RNA-seq data (8,24).…”

Helminths and intestinal barrier function

“…The potential of helminth-evoked changes in the enteric nervous system 95 and the regulation of mucus production by acetylcholine should also be pursued. 96 Finally, recent work has shown that goblet cells can sense their microenvironment and pass this information to dendritic cells; 97 the implications of this for barrier function and host-parasite interactions are poorly understood.…”