title: Lymphocyte Circadian Clocks Control Lymph Node Trafficking and Adaptive Immune Responses.
abstract: Lymphocytes circulate through lymph nodes (LN) in search for antigen in what is believed to be a continuous process. Here, we show that lymphocyte migration through lymph nodes and lymph occurred in a non-continuous, circadian manner. Lymphocyte homing to lymph nodes peaked at night onset, with cells leaving the tissue during the day. This resulted in strong oscillations in lymphocyte cellularity in lymph nodes and efferent lymphatic fluid. Using lineage-specific genetic ablation of circadian clock function, we demonstrated this to be dependent on rhythmic expression of promigratory factors on lymphocytes. Dendritic cell numbers peaked in phase with lymphocytes, with diurnal oscillations being present in disease severity after immunization to induce experimental autoimmune encephalomyelitis (EAE). These rhythms were abolished by genetic disruption of T cell clocks, demonstrating a circadian regulation of lymphocyte migration through lymph nodes with time-of-day of immunization being critical for adaptive immune responses weeks later.
authors.affiliation: BioMedical Center, Walter-Brendel-Centre for Experimental Medicine, Ludwig-Maximilians-University, 82152 Planegg-Martinsried, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Druzd
authors.affiliation: Medical Department I, University of Lübeck, 23562 Lübeck, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Matveeva
authors.affiliation: BioMedical Center, Walter-Brendel-Centre for Experimental Medicine, Ludwig-Maximilians-University, 82152 Planegg-Martinsried, Germany.
authors.forename: Louise
authors.initials: L
authors.lastname: Ince
authors.affiliation: Max von Pettenkofer-Institute for Hygiene and Medical Microbiology, Ludwig-Maximilians-University, 80336 Munich, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Harrison
authors.affiliation: BioMedical Center, Walter-Brendel-Centre for Experimental Medicine, Ludwig-Maximilians-University, 82152 Planegg-Martinsried, Germany.
authors.forename: Wenyan
authors.initials: W
authors.lastname: He
authors.affiliation: Charité University Hospital Berlin, 10117 Berlin, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schmal
authors.affiliation: Institute for Theoretical Biology, Humboldt University of Berlin, 10115 Berlin, Germany.
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Herzel
authors.affiliation: Medical Department I, University of Lübeck, 23562 Lübeck, Germany.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Tsang
authors.affiliation: BioMedical Center, Institute of Clinical Neuroimmunology, Ludwig-Maximilians-University, 82152 Planegg-Martinsried, Germany.
authors.forename: Naoto
authors.initials: N
authors.lastname: Kawakami
authors.affiliation: Laboratory of Immunology, Institute for Nutrition Medicine, University of Lübeck, 23562 Lübeck, Germany.
authors.forename: Alexei
authors.initials: A
authors.lastname: Leliavski
authors.affiliation: Ludwig-Maximilians-University, Dr. von Hauner Children's Hospital, University of Munich Medical Center, 80337 Munich, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Uhl
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité University Hospital Berlin, 10117 Berlin, Germany.
authors.forename: Ling
authors.initials: L
authors.lastname: Yao
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité University Hospital Berlin, 10117 Berlin, Germany.
authors.forename: Leif Erik
authors.initials: LE
authors.lastname: Sander
authors.affiliation: BioMedical Center, Walter-Brendel-Centre for Experimental Medicine, Ludwig-Maximilians-University, 82152 Planegg-Martinsried, Germany.
authors.forename: Chien-Sin
authors.initials: CS
authors.lastname: Chen
authors.affiliation: BioMedical Center, Walter-Brendel-Centre for Experimental Medicine, Ludwig-Maximilians-University, 82152 Planegg-Martinsried, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kraus
authors.affiliation: BioMedical Center, Walter-Brendel-Centre for Experimental Medicine, Ludwig-Maximilians-University, 82152 Planegg-Martinsried, Germany.
authors.forename: Alba
authors.initials: A
authors.lastname: de Juan
authors.affiliation: BioMedical Center, Walter-Brendel-Centre for Experimental Medicine, Ludwig-Maximilians-University, 82152 Planegg-Martinsried, Germany.
authors.forename: Sophia Martina
authors.initials: SM
authors.lastname: Hergenhan
authors.affiliation: Laboratory of Immunology, Institute for Nutrition Medicine, University of Lübeck, 23562 Lübeck, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Ehlers
authors.affiliation: Ludwig-Maximilians-University, Dr. von Hauner Children's Hospital, University of Munich Medical Center, 80337 Munich, Germany.
authors.forename: Berthold
authors.initials: B
authors.lastname: Koletzko
authors.affiliation: Max von Pettenkofer-Institute for Hygiene and Medical Microbiology, Ludwig-Maximilians-University, 80336 Munich, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Haas
authors.affiliation: Center for Infection and Inflammation, University of Lübeck, 23562 Lübeck, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Solbach
authors.affiliation: Medical Department I, University of Lübeck, 23562 Lübeck, Germany.
authors.forename: Henrik
authors.initials: H
authors.lastname: Oster
authors.affiliation: BioMedical Center, Walter-Brendel-Centre for Experimental Medicine, Ludwig-Maximilians-University, 82152 Planegg-Martinsried, Germany. Electronic address: christoph.scheiermann@med.uni-muenchen.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Scheiermann
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D019264:Adoptive Transfer; D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D057906:Circadian Clocks / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007157:Immunologic Surveillance / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction
keywords: adaptive immune response; circadian rhythm; immunization; leukocyte trafficking; lymph node egress; lymph node homing