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      Dendritic Cells Control Fibroblastic Reticular Network Tension and Lymph Node Expansion

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          Abstract

          Following immunogenic challenge, infiltrating and dividing lymphocytes significantly increase lymph node (LN) cellularity leading to organ expansion 1, 2 . Here we report that the physical elasticity of LNs is maintained in part by podoplanin (PDPN) signalling in stromal fibroblastic reticular cells (FRCs) and its modulation by CLEC-2 expressed on dendritic cells (DCs). We show that PDPN induces actomyosin contractility in FRCs via activation of RhoA/C and downstream Rho-kinase. Engagement by CLEC-2 causes PDPN clustering and rapidly uncouples PDPN from RhoA/C activation, relaxing the actomyosin cytoskeleton and permitting FRC stretching. Notably, administration of CLEC-2 protein to immunised mice augments LN expansion. In contrast, the latter is significantly constrained in mice selectively lacking CLEC-2 expression in DCs. Thus, the same DCs that initiate immunity by presenting antigens to T lymphocytes 3 also initiate remodeling of LNs by delivering CLEC-2 to FRCs. CLEC-2 modulation of PDPN signalling permits FRC network stretching and allows for the rapid LN expansion driven by lymphocyte influx and proliferation that is the critical hallmark of adaptive immunity.

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          Most cited references21

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          Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells.

          Interleukin 7 is essential for the survival of naive T lymphocytes. Despite its importance, its cellular source in the periphery remains poorly defined. Here we report a critical function for lymph node access in T cell homeostasis and identify T zone fibroblastic reticular cells in these organs as the main source of interleukin 7. In vitro, T zone fibroblastic reticular cells were able to prevent the death of naive T lymphocytes but not of B lymphocytes by secreting interleukin 7 and the CCR7 ligand CCL19. Using gene-targeted mice, we demonstrate a nonredundant function for CCL19 in T cell homeostasis. Our data suggest that lymph nodes and T zone fibroblastic reticular cells have a key function in naive CD4(+) and CD8(+) T cell homeostasis by providing a limited reservoir of survival factors.
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            The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node.

            Resident dendritic cells (DC) within the T cell area of the lymph node take up soluble antigens that enter via the afferent lymphatics before antigen carrying DC arrive from the periphery. The reticular network within the lymph node is a conduit system forming the infrastructure for the fast delivery of soluble substances from the afferent lymph to the lumen of high endothelial venules (HEVs). Using high-resolution light microscopy and 3D reconstruction, we show here that these conduits are unique basement membrane-like structures ensheathed by fibroblastic reticular cells with occasional resident DC embedded within this cell layer. Conduit-associated DC are capable of taking up and processing soluble antigens transported within the conduits, whereas immigrated mature DC occur remote from the reticular fibers. The conduit system is, therefore, not a closed compartment that shuttles substances through the lymph node but represents the morphological equivalent to the filtering function of the lymph node.
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              The actin cytoskeleton in cancer cell motility.

              Cancer cell metastasis is a multi-stage process involving invasion into surrounding tissue, intravasation, transit in the blood or lymph, extravasation, and growth at a new site. Many of these steps require cell motility, which is driven by cycles of actin polymerization, cell adhesion and acto-myosin contraction. These processes have been studied in cancer cells in vitro for many years, often with seemingly contradictory results. The challenge now is to understand how the multitude of in vitro observations relates to the movement of cancer cells in living tumour tissue. In this review we will concentrate on actin protrusion and acto-myosin contraction. We will begin by presenting some general principles summarizing the widely-accepted mechanisms for the co-ordinated regulation of actin polymerization and contraction. We will then discuss more recent studies that investigate how experimental manipulation of actin dynamics affects cancer cell invasion in complex environments and in vivo.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                14 November 2014
                23 October 2014
                23 April 2015
                : 514
                : 7523
                : 498-502
                Affiliations
                [1 ]Immunobiology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London, WC2A 3LY, UK
                [2 ]Department of Cell and Developmental Biology, University College London, Gower Street, WC1E 6BT, UK
                [3 ]Tumour Cell Biology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London, WC2A 3LY, UK
                [4 ]Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02215, USA
                [5 ]Experimental Histopathology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London, WC2A 3LY, UK
                [6 ]Transgenics Laboratory, Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Potters Bar, Hertfordshire, EN6 3LD, UK
                [7 ]Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal and Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
                Author notes
                Correspondence and requests for materials should be addressed to S.E.A. ( sophie.acton@ 123456cancer.org.uk ) or C.R.S. ( caetano@ 123456cancer.org.uk )
                [*]

                Current address: Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA

                Author Contributions: S.E.A, E.S. and C.R.S. designed the study, analysed data and wrote the manuscript. S.E.A. conducted experiments with assistance from A.J.F., J.v.B., R.P.J. K.J.S. and S.H. Preliminary results were generated with S.J.T. and J.L.A. E.N. and G.S. carried out immunohistochemistry and morphometric analysis. D.M.S., N.C.R and I.R. generated CD11c Δ CLEC-2 mice. N.C.R. managed breeding and genotyping of mouse strains. L.F.M. provided key reagents.

                Article
                EMS60233
                10.1038/nature13814
                4235005
                25341788
                db4d1637-baf9-4a67-ae02-de069341b090
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