| Summary: | Summary: The monocyte-derived phagocytes termed LysoDCs are hallmarks of Peyer’s patches, where their main function is to sample intestinal microorganisms. Here, we study their differentiation pathways in relation with their sampling, migratory, and T cell-priming abilities. Among four identified LysoDC differentiation stages displaying similar phagocytic activity, one is located in follicles, and the others reside in subepithelial domes (SED), where they proliferate and mature as they get closer to the epithelium. Mature LysoDCs but not macrophages express a gene set in common with conventional dendritic cells and prime naive helper T cells in vitro. At steady state, they do not migrate into naive T cell-enriched interfollicular regions (IFRs), but upon stimulation, they express the chemokine receptor CCR7 and migrate from SED to the IFR periphery, where they strongly interact with proliferative immune cells. Finally, we show that LysoDCs populate human Peyer’s patches, strengthening their interest as targets for modulating intestinal immunity. : Wagner et al. dissect the differentiation pathways of the Peyer’s patch monocyte-derived dendritic cells termed LysoDCs. They show that LysoDCs mature as they get closer to the epithelium. Mature LysoDCs migrate to the periphery of the T cell zone, where proliferation of immune cells occurs only when stimulated. Keywords: intestinal immunity, Peyer’s patches, phagocytes, dendritic cells, monocyte-derived cells, LysoDC, cell differentiation, single-cell RNA sequencing, antigen sampling, naive T cell priming
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