Circadian clocks guide dendritic cells into skin lymphatics

• Published in: Nature immunology Vol. 22; no. 11; pp. 1375 - 1381
• Main Authors: Holtkamp, Stephan J., Ince, Louise M., Barnoud, Coline, Schmitt, Madeleine T., Sinturel, Flore, Pilorz, Violetta, Pick, Robert, Jemelin, Stéphane, Mühlstädt, Michael, Boehncke, Wolf-Henning, Weber, Jasmin, Laubender, David, Philippou-Massier, Julia, Chen, Chien-Sin, Holtermann, Leonie, Vestweber, Dietmar, Sperandio, Markus, Schraml, Barbara U., Halin, Cornelia, Dibner, Charna, Oster, Henrik, Renkawitz, Jörg, Scheiermann, Christoph
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2021; Nature Publishing Group
• Subjects: 631/250/1617/2069; 631/250/2152; Adaptive Immunity; Aged; Animals; Biomedical and Life Sciences; Biomedicine; CCL21 protein; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cells; Cells, Cultured; Chemokine CCL21 - genetics; Chemokine CCL21 - metabolism; Chemokines; Chemotaxis; Circadian Clocks; Circadian rhythm; Circadian Rhythm Signaling Peptides and Proteins - genetics; Circadian Rhythm Signaling Peptides and Proteins - metabolism; Circadian rhythms; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Endothelial cells; Female; Health aspects; Humans; Immunological research; Immunology; Immunotherapy; Infectious Diseases; Infiltration; Letter; Leukocyte migration; Lymph nodes; Lymph Nodes - immunology; Lymph Nodes - metabolism; Lymphatic system; Lymphatic Vessels - immunology; Lymphatic Vessels - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motility; Oscillations; Physiological aspects; Sensory neurons; Skin; Skin - immunology; Skin - metabolism; Time Factors; Vaccination; Germany
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/s41590-021-01040-x

Migration of leukocytes from the skin to lymph nodes (LNs) via afferent lymphatic vessels (LVs) is pivotal for adaptive immune responses 1 , 2 . Circadian rhythms have emerged as important regulators of leukocyte trafficking to LNs via the blood 3 , 4 . Here, we demonstrate that dendritic cells (DCs) have a circadian migration pattern into LVs, which peaks during the rest phase in mice. This migration pattern is determined by rhythmic gradients in the expression of the chemokine CCL21 and of adhesion molecules in both mice and humans. Chronopharmacological targeting of the involved factors abrogates circadian migration of DCs. We identify cell-intrinsic circadian oscillations in skin lymphatic endothelial cells (LECs) and DCs that cogovern these rhythms, as their genetic disruption in either cell type ablates circadian trafficking. These observations indicate that circadian clocks control the infiltration of DCs into skin lymphatics, a process that is essential for many adaptive immune responses and relevant for vaccination and immunotherapies. Scheiermann and colleagues show that circadian clocks control the infiltration of dendritic cells into skin lymphatics in mice and humans, with a peak migration to the lymph nodes during the rest phase.