Nat Immunol. 2021 Nov;22(11):1375-1381. doi: 10.1038/s41590-021-01040-x. | PubMed

Stephan J Holtkamp¹, Louise M Ince², Coline Barnoud², Madeleine T Schmitt^1,3, Flore Sinturel^4,5,6,7, Violetta Pilorz⁸, Robert Pick², Stéphane Jemelin², Michael Mühlstädt⁹, Wolf-Henning Boehncke^2,9, Jasmin Weber¹, David Laubender¹⁰, Julia Philippou-Massier¹¹, Chien-Sin Chen¹, Leonie Holtermann¹², Dietmar Vestweber¹², Markus Sperandio¹, Barbara U Schraml¹, Cornelia Halin¹³, Charna Dibner^4,5,6,7, Henrik Oster⁸, Jörg Renkawitz^1,3, Christoph Scheiermann^14,15

1. Biomedical Center (BMC), Institute for Cardiovascular Physiology and Pathophysiology, Walter Brendel Center for Experimental Medicine (WBex), Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Planegg-Martinsried, Germany.
2. Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
3. Laboratory 'Cell Biology of the Immune System', Biomedical Center (BMC), Institute for Cardiovascular Physiology and Pathophysiology, Walter Brendel Center for Experimental Medicine (WBex), Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Planegg-Martinsried, Germany.
4. Department of Medicine, Division of Endocrinology, Diabetes, Nutrition and Patient Education, University Hospitals of Geneva, Geneva, Switzerland.
5. Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
6. Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
7. Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland.
8. Institute of Neurobiology, University of Lübeck, Lübeck, Germany.
9. Division of Dermatology and Venereology, Department of Medicine, University Hospitals of Geneva, Geneva, Switzerland.
10. Max Planck Institute of Neurobiology, Martinsried, Germany.
11. Laboratory for Functional Genome Analysis, Gene Center Munich, Ludwig-Maximilians-Universität Munich, Munich, Germany.
12. Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
13. Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland.
14. Biomedical Center (BMC), Institute for Cardiovascular Physiology and Pathophysiology, Walter Brendel Center for Experimental Medicine (WBex), Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Planegg-Martinsried, Germany. christoph.scheiermann@unige.ch.
15. Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. christoph.scheiermann@unige.ch.

Abstract

Migration of leukocytes from the skin to lymph nodes (LNs) via afferent lymphatic vessels (LVs) is pivotal for adaptive immune responses1,2. Circadian rhythms have emerged as important regulators of leukocyte trafficking to LNs via the blood3,4. 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.

Presented By Christoph Scheiermann