The small intestine (SI) epithelium is a major interface between the body and the environment. In addition to nutrient absorption, this single layer epithelium must act as a barrier to pathogenic infection while allowing the underlying immune system to selectively sample antigens from the normal flora and the diet to promote homeostasis. How the epithelium simultaneously performs these opposing tasks is a fundamental question in mucosal immunology. Recently, it was discovered that when goblet cells (GCs) secrete, they form goblet cell-associated antigen passages (GAPs) that can deliver small soluble luminal antigens to lamina propria (LP) dendritic cells (DCs). 1 This striking observation suggests that GCs have a previously unappreciated role in regulating adaptive immune responses at the mucosa and provides important insight into how the epithelium can maintain its barrier function, while allowing LP-DCs to sample the intestinal contents. The SI LP is densely populated by macrophages and DCs, with various subsets contributing to inflammation, tolerance and adaptive immunity. Antigen presentation is a central function of DCs, thus it has been assumed that

LP-DCs have the ability to capture antigen from the epithelium and even the lumen of the intestine. Several mechanisms have been identified for the delivery of luminal antigens to LP-DCs, including paracellular leak, villous microfold cells (M cells), and trans-epithelial dendrite (TED) extension by LP-DCs. However, the relative contribution of each of these pathways and the context in which they contribute to downstream immune responses has been largely unexplored. Using in vivo two-photon microscopy, McDole et al. examined the steadystate uptake of fluorescently labeled soluble antigens across the SI epithelium and found that a subset of epithelial cells rapidly filled with luminal antigen. Time-lapse movies showed that LP-DCs actively probed these epithelial cells and could acquire antigen from them directly, whereas antigen capture via paracellular leak was undetectable microscopically. Subsequently, the antigen-containing epithelial cells were shown to be GCs, and multiple approaches confirmed that GCs effectively delivered small (o70 kD) soluble luminal antigens to underlying LP-DCs. In mice that lack GCs, luminal antigen acquisition and presentation by LP-DCs