Ince and Barnoud et al. showed that antigen challenge of mice near the start of behavioral activity (“daytime” - start of darkness for nocturnal species) compared to “night-time” induced greater integrin-dependent increases in homing, contact, and proliferation of BMDCs and lymphocytes in dLNs. Challenge of mice with selective deficiency of the core circadian TF, BMAL1, shown to bind the Icam1 promoter, showed it controlled diurnal changes in ICAM-1 HEV expression, which were enhanced by rhythmic TNF expression. T cell BMAL1 deficiency also ablated diurnal effects. The impact of time of initial challenge was imprinted on subsequent immune processes underlying adaptive murine responses to two human vaccines.
Contributed by Paula Hochman
ABSTRACT: The adaptive immune response is under circadian control, yet, why adaptive immune reactions continue to exhibit circadian changes over long periods of time is unknown. Using a combination of experimental and mathematical modeling approaches, we show here that dendritic cells migrate from the skin to the draining lymph node in a time-of-day-dependent manner, which provides an enhanced likelihood for functional interactions with T cells. Rhythmic expression of TNF in the draining lymph node enhances BMAL1-controlled ICAM-1 expression in high endothelial venules, resulting in lymphocyte infiltration and lymph node expansion. Lymph node cellularity continues to be different for weeks after the initial time-of-day-dependent challenge, which governs the immune response to vaccinations directed against Hepatitis A virus as well as SARS-CoV-2. In this work, we present a mechanistic understanding of the time-of-day dependent development and maintenance of an adaptive immune response, providing a strategy for using time-of-day to optimize vaccination regimes.
Author Info: (1) Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. Division of Pharmacology & Toxicology, College of Pharmacy, University o
Author Info: (1) Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. Division of Pharmacology & Toxicology, College of Pharmacy, University of Texas at Austin, Austin, TX, USA. (2) Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. (3) Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. (4) Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. (5) Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. (6) Department of Medicine, Division of Endocrinology, Diabetes, Nutrition and Patient Education, Faculty of Medicine, University of Geneva, Geneva, Switzerland. Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland. Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland. (7) Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-University Munich, BioMedical Centre, Planegg-Martinsried, Germany. (8) Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-University Munich, BioMedical Centre, Planegg-Martinsried, Germany. (9) Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-University Munich, BioMedical Centre, Planegg-Martinsried, Germany. (10) Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-University Munich, BioMedical Centre, Planegg-Martinsried, Germany. (11) Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-University Munich, BioMedical Centre, Planegg-Martinsried, Germany. (12) Experimental Systems Immunology, Max Planck Institute of Biochemistry, Martinsried, Germany. Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada. (13) Experimental Systems Immunology, Max Planck Institute of Biochemistry, Martinsried, Germany. Systems Immunology and Proteomics, Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany. (14) Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. World Health Organization Collaborating Center for Vaccine Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. (15) Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. World Health Organization Collaborating Center for Vaccine Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. (16) Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. World Health Organization Collaborating Center for Vaccine Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. (17) Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. (18) Department of Medicine, Division of Endocrinology, Diabetes, Nutrition and Patient Education, Faculty of Medicine, University of Geneva, Geneva, Switzerland. Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland. Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland. (19) Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. World Health Organization Collaborating Center for Vaccine Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. (20) Experimental Systems Immunology, Max Planck Institute of Biochemistry, Martinsried, Germany. Systems Immunology and Proteomics, Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany. (21) BioQuant - Center for Quantitative Biology, Heidelberg University, Heidelberg, Germany. Interdisciplinary Center for Scientific Computing, Heidelberg University, Heidelberg, Germany. (22) Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. christoph.scheiermann@unige.ch. Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland. christoph.scheiermann@unige.ch. Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-University Munich, BioMedical Centre, Planegg-Martinsried, Germany. christoph.scheiermann@unige.ch. Geneva Centre for Inflammation Research, Faculty of Medicine, University of Geneva, Geneva, Switzerland. christoph.scheiermann@unige.ch.
