Cell Migration Promotes the Functional Diversification of Gut Dendritic Cells

Dendritic cells (DCs) patrol tissues and transport antigens to lymph nodes to initiate adaptive immune responses. Within tissues, DCs constitute a complex cell population made of distinct subsets that express different markers and eventually display different functions. How cell-intrinsic programs and tissue-specific cues orchestrate DC diversification is only partially understood. By combining single-cell sequencing and intravital imaging, we here show that DC migration to the small intestine epithelium leads to the generation of an “immature-like” intraepithelial pool of cDC2s. These cells exhibit tolerogenic properties in contrast to lamina propria DCs, which are pro-inflammatory, resembling mature DCs. We further identify the actin motor myosin II and the nutrient-derived metabolite retinoic acid as the cell-intrinsic and -extrinsic cues driving the formation of this intraepithelial pool of cDC2s. Together, these results show that fine-tuning of DC migration controls their functional diversification within tissues.