Locally Triggered Release of the Chemokine CCL21 Promotes Dendritic Cell Transmigration across Lymphatic Endothelia

Trafficking cells frequently transmigrate through epithelial and endothelial monolayers. How monolayers cooperate with the penetrating cells to support their transit is poorly understood. We studied dendritic cell (DC) entry into lymphatic capillaries as a model system for transendothelial migration. We find that the chemokine CCL21, which is the decisive guidance cue for intravasation, mainly localizes in the trans-Golgi network and intracellular vesicles of lymphatic endothelial cells. Upon DC transmigration, these Golgi deposits disperse and CCL21 becomes extracellularly enriched at the sites of endothelial cell-cell junctions. When we reconstitute the transmigration process in vitro, we find that secretion of CCL21-positive vesicles is triggered by a DC contact-induced calcium signal, and selective calcium chelation in lymphatic endothelium attenuates transmigration. Altogether, our data demonstrate a chemokine-mediated feedback between DCs and lymphatic endothelium, which facilitates transendothelial migration. [Display omitted] •DC entry into lymphatic capillary induces CCL21 secretion to endothelial junctions•Chemokine CCL21 secretion is triggered by calcium fluxes•Direct contact by DC induces calcium signaling in LECs•Dynamic rather than pre-patterned chemokine CCL21 cues promote DC transmigration Antigen-presenting dendritic cells approach and enter lymphatic capillaries in a chemokine CCL21-dependent manner. Vaahtomeri et al. show that migrating dendritic cells trigger chemokine-mediated feedback via direct contact with lymphatic endothelia, which locally release CCL21 and thus promote transmigration.