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      Lymphocyte Circadian Clocks Control Lymph Node Trafficking and Adaptive Immune Responses

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          Summary

          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.

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          Highlights

          • Lymphocyte numbers in lymph nodes and lymph oscillate over the course of the day

          • Rhythmic Ccr7 and S1pr1 expression drives rhythmic lymphocyte homing and egress

          • Adaptive immune responses to immunization and pathogens are time-of-day dependent

          • Loss of circadian clocks in lymphocytes ablates rhythmic adaptive immune responses

          Abstract

          Lymphocyte trafficking through lymph nodes and lymph is an important immune surveillance mechanism of the body. Druzd et al. (2017) demonstrate that this trafficking occurs in a circadian manner and that adaptive immune responses are also time-of-day dependent and are ablated when circadian clock function is lost in T cells.

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          Most cited references21

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          Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1.

          Adaptive immunity depends on T-cell exit from the thymus and T and B cells travelling between secondary lymphoid organs to survey for antigens. After activation in lymphoid organs, T cells must again return to circulation to reach sites of infection; however, the mechanisms regulating lymphoid organ exit are unknown. An immunosuppressant drug, FTY720, inhibits lymphocyte emigration from lymphoid organs, and phosphorylated FTY720 binds and activates four of the five known sphingosine-1-phosphate (S1P) receptors. However, the role of S1P receptors in normal immune cell trafficking is unclear. Here we show that in mice whose haematopoietic cells lack a single S1P receptor (S1P1; also known as Edg1) there are no T cells in the periphery because mature T cells are unable to exit the thymus. Although B cells are present in peripheral lymphoid organs, they are severely deficient in blood and lymph. Adoptive cell transfer experiments establish an intrinsic requirement for S1P1 in T and B cells for lymphoid organ egress. Furthermore, S1P1-dependent chemotactic responsiveness is strongly upregulated in T-cell development before exit from the thymus, whereas S1P1 is downregulated during peripheral lymphocyte activation, and this is associated with retention in lymphoid organs. We find that FTY720 treatment downregulates S1P1, creating a temporary pharmacological S1P1-null state in lymphocytes, providing an explanation for the mechanism of FTY720-induced lymphocyte sequestration. These findings establish that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.
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            CCR7 and its ligands: balancing immunity and tolerance.

            A key feature of the immune system is its ability to induce protective immunity against pathogens while maintaining tolerance towards self and innocuous environmental antigens. Recent evidence suggests that by guiding cells to and within lymphoid organs, CC-chemokine receptor 7 (CCR7) essentially contributes to both immunity and tolerance. This receptor is involved in organizing thymic architecture and function, lymph-node homing of naive and regulatory T cells via high endothelial venules, as well as steady state and inflammation-induced lymph-node-bound migration of dendritic cells via afferent lymphatics. Here, we focus on the cellular and molecular mechanisms that enable CCR7 and its two ligands, CCL19 and CCL21, to balance immunity and tolerance.
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              Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs.

              Much has been learned about how cells enter lymphoid tissues. But how do they leave? Sphingosine-1-phosphate (S1P) has emerged over the past decade as a central mediator of lymphocyte egress. In this review, we summarize the current understanding of how S1P promotes exit from the secondary lymphoid organs and thymus. We review what is known about additional requirements for emigration and summarize the mostly distinct requirements for exit from the bone marrow. Egress from lymphoid organs is limited during immune responses, and we examine how this regulation works. There is accumulating evidence for roles of S1P in directing immune cell behavior within lymphoid tissues. How such actions can fit together with the egress-promoting role of S1P is discussed. Finally, we examine current understanding of how FTY720, a drug that targets S1P receptors and is approved for the treatment of multiple sclerosis, causes immune suppression.
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                Author and article information

                Contributors
                Journal
                Immunity
                Immunity
                Immunity
                Cell Press
                1074-7613
                1097-4180
                17 January 2017
                17 January 2017
                : 46
                : 1
                : 120-132
                Affiliations
                [1 ]BioMedical Center, Walter-Brendel-Centre for Experimental Medicine, Ludwig-Maximilians-University, 82152 Planegg-Martinsried, Germany
                [2 ]Medical Department I, University of Lübeck, 23562 Lübeck, Germany
                [3 ]Max von Pettenkofer-Institute for Hygiene and Medical Microbiology, Ludwig-Maximilians-University, 80336 Munich, Germany
                [4 ]Charité University Hospital Berlin, 10117 Berlin, Germany
                [5 ]Institute for Theoretical Biology, Humboldt University of Berlin, 10115 Berlin, Germany
                [6 ]BioMedical Center, Institute of Clinical Neuroimmunology, Ludwig-Maximilians-University, 82152 Planegg-Martinsried, Germany
                [7 ]Laboratory of Immunology, Institute for Nutrition Medicine, University of Lübeck, 23562 Lübeck, Germany
                [8 ]Ludwig-Maximilians-University, Dr. von Hauner Children’s Hospital, University of Munich Medical Center, 80337 Munich, Germany
                [9 ]Department of Infectious Diseases and Pulmonary Medicine, Charité University Hospital Berlin, 10117 Berlin, Germany
                [10 ]Center for Infection and Inflammation, University of Lübeck, 23562 Lübeck, Germany
                Author notes
                [11]

                Co-first author

                [12]

                Lead Contact

                Article
                S1074-7613(16)30517-9
                10.1016/j.immuni.2016.12.011
                5263259
                28087238
                07a2290c-a5af-458b-a639-a4ff57d189b8
                © 2017 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 2 July 2016
                : 24 October 2016
                : 18 November 2016
                Categories
                Article

                Immunology
                circadian rhythm,leukocyte trafficking,adaptive immune response,lymph node homing,lymph node egress,immunization

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