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The intestine is a specialized environment in which immune cells must defend the body against pathogens while ignoring beneficial commensal bacteria. Specialized epithelial cells known as microfold (M) cells can sample luminal antigens and pass them to dendritic cells (DCs). Other studies have shown that DCs can directly sample luminal antigens. Now, Hans-Christian Reinecker and colleagues describe a network of myeloid-derived CX₃C-chemokine receptor 1 (CX₃CR1)⁺ DCs in the lamina propria that can also directly sample luminal antigens.

To study phagocytic cells in the intestine, the authors used mice in which one or both copies of the gene encoding CX₃CR1 — the product of which binds the transmembrane chemokine CX₃C-chemokine ligand 1 (CX₃CL1) expressed by intestinal epithelial and endothelial cells — were replaced with a gene encoding green fluorescent protein (GFP). Heterozygous mice (Cx₃cr1^GFP/+) express both GFP and the chemokine receptor, whereas homozygous mice (Cx₃cr1^GFP/GFP) express only GFP. GFP⁺ monocytic cells were observed in the lamina propria, mesenteric lymph nodes and Peyer's patches. GFP⁺ lamina-propria DCs expressed CD11c and CD11b, as well as MHC class II and the co-stimulatory molecules CD80 and CD86.

The authors used confocal microscopy to look at the distribution of intestinal DCs and their interactions with epithelial cells. In the terminal ileum of Cx₃cr1^GFP/+ mice, lamina-propria DCs extended dendrites into the intestinal lumen. By contrast, in Cx₃cr1^GFP/GFP mice, dendrites could form in the lamina-propria layer but did not extend into the intestinal lumen, indicating that transepithelial dendrite formation is a CX₃CR1-dependent process. Three-dimensional tissue reconstructions based on confocal images showed that the dendrites that extended into the lumen ended in mono- or multi-globular structures. The authors then examined the role of CX₃CR1⁺ DCs in the sampling of the commensal microflora and during infection with the pathogenic bacterium Salmonella typhimurium. Cx₃cr1^GFP/GFP mice were more susceptible to infection than heterozygous mice, probably as a result of impaired bacterial sampling and lack of transepithelial dendrites.

This study describes a network of lamina-propria DCs that can directly sample luminal antigens using a mechanism distinct from that involving M cells. It remains to be determined which antigen-uptake receptors are expressed at the terminal dendrite structures and whether commensal bacteria can be distinguished from pathogens, but the authors suggest that it might be possible to target these structures to engage intestinal DCs, which could be useful for vaccine development.