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      Podoplanin-Rich Stromal Networks Induce Dendritic Cell Motility via Activation of the C-type Lectin Receptor CLEC-2

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          Summary

          To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces.

          Highlights

          ► The CLEC-2-PDPN interaction promotes DC migration to LNs ► CLEC-2 activation induces actin-rich protrusions and motility in DCs ► CLEC-2 activation reduces actomyosin contraction and promotes actin polymerization

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

          Alexander Link, Tobias K. Vogt, Stéphanie Favre … (2007)
          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.
          Article 0 comments Cited 310 times – based on 0 reviews     Review now
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            The actin cytoskeleton in cancer cell motility.

            Michael Olson, Erik Sahai (2009)
            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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              ROCK- and myosin-dependent matrix deformation enables protease-independent tumor-cell invasion in vivo.

              Jeffrey B Wyckoff, Sophie Pinner, Steve E. Gschmeissner … (2006)
              Tumor cells invading three-dimensional matrices need to remodel the extracellular matrix (ECM) in their path. Many studies have focused on the role of extracellular proteases; however, cells with amoeboid or rounded morphologies are able to invade even when these enzymes are inhibited. Here, we describe the mechanism by which cells move through a dense ECM without proteolysis. Amoeboid tumor cells generate sufficient actomyosin force to deform collagen fibers and are able to push through the ECM. Force generation is elevated in metastatic MTLn3E cells, and this correlates with increased invasion and altered myosin light chain (MLC) organization. In metastatic cells, MLC is organized perpendicularly to the direction of movement behind the invading edge. Both the organization of MLC and force generation are dependent upon ROCK function. We demonstrate that ROCK regulates the phosphorylation of MLC just behind the invading margin of the cell. Imaging of live tumors shows that MLC is organized in a similar ROCK-dependent fashion in vivo and that inhibition of ROCK but not matrix-metalloproteases reduces cancer cell motility in vivo.
              Article 0 comments Cited 130 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Immunity
                Journal ID (iso-abbrev): Immunity
                Title: Immunity
                Publisher: Cell Press
                ISSN (Print): 1074-7613
                ISSN (Electronic): 1097-4180
                Publication date PMC-release: 24 August 2012
                Publication date (Print): 24 August 2012
                Volume: 37
                Issue: 2
                Pages: 276-289
                Affiliations
                [1 ]Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02215, USA
                [2 ]Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK
                [3 ]Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA
                [4 ]Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
                [5 ]Immune Disease Institute and Program in Cellular and Molecular Medicine, Children’s Hospital, Departments of Pediatrics and Pathology, Harvard Medical School, Boston, MA 02115, USA
                [6 ]Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
                [7 ]Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
                [8 ]Department of Biochemistry, Meiji Pharmaceutical University, Kiyose, Tokyo 204-8588, Japan
                [9 ]Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA
                Author notes
                [∗ ]Corresponding author shannon_turley@ 123456dfci.harvard.edu
                [10]

                These authors contributed equally to this work

                Article
                Publisher ID: IMMUNI2404
                DOI: 10.1016/j.immuni.2012.05.022
                PMC ID: 3556784
                PubMed ID: 22884313
                SO-VID: b94b3df6-04ac-474f-951d-1995c2c9f159
                Copyright © © 2012 ELL & Excerpta Medica.
                License:

                This document may be redistributed and reused, subject to certain conditions.

                History
                Date received : 27 September 2011
                Date revision received : 18 April 2012
                Date accepted : 12 May 2012
                Categories
                Subject: Article

                ScienceOpen disciplines: Immunology
                Data availability:
                ScienceOpen disciplines: Immunology

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