Podosomes of dendritic cells facilitate antigen sampling

ABSTRACT Dendritic cells sample the environment for antigens and play an important role in establishing the link between innate and acquired immunity. Dendritic cells contain mechanosensitive adhesive structures called podosomes that consist of an actin-rich core surrounded by integrins, adaptor proteins and actin network filaments. They facilitate cell migration via localized degradation of extracellular matrix. Here, we show that podosomes of human dendritic cells locate to spots of low physical resistance in the substrate (soft spots) where they can evolve into protrusive structures. Pathogen recognition receptors locate to these protrusive structures where they can trigger localized antigen uptake, processing and presentation to activate T-cells. Our data demonstrate a novel role in antigen sampling for the podosomes of dendritic cells.

[1]  John Condeelis,et al.  Directed cell invasion and migration during metastasis. , 2012, Current opinion in cell biology.

[2]  J. Sanes,et al.  Podosomes are present in a postsynaptic apparatus and participate in its maturation , 2009, Proceedings of the National Academy of Sciences.

[3]  Roberto Buccione,et al.  Foot and mouth: podosomes, invadopodia and circular dorsal ruffles , 2004, Nature Reviews Molecular Cell Biology.

[4]  D. Philpott,et al.  Mammalian NLR proteins; discriminating foe from friend , 2007, Immunology and cell biology.

[5]  C. Figdor,et al.  Ligand-conjugated quantum dots monitor antigen uptake and processing by dendritic cells. , 2007, Nano letters.

[6]  S. Gordon,et al.  Ligand recognition by antigen-presenting cell C-type lectin receptors , 2004, Current Opinion in Immunology.

[7]  S. Kurisu,et al.  Antagonistic regulation of F-BAR protein assemblies controls actin polymerization during podosome formation , 2013, Journal of Cell Science.

[8]  V. Lukacs-Kornek,et al.  The Mannose Receptor Mediates Uptake of Soluble but Not of Cell-Associated Antigen for Cross-Presentation1 , 2006, The Journal of Immunology.

[9]  Hayder Amin,et al.  Membrane protein sequestering by ionic protein-lipid interactions , 2011, Nature.

[10]  W. Muller,et al.  Mechanisms of leukocyte transendothelial migration. , 2011, Annual review of pathology.

[11]  Robert D. Goldman,et al.  Actin, microtubules, and vimentin intermediate filaments cooperate for elongation of invadopodia , 2010, The Journal of cell biology.

[12]  Hugues Lelouard,et al.  Peyer's patch dendritic cells sample antigens by extending dendrites through M cell-specific transcellular pores. , 2012, Gastroenterology.

[13]  J. Faix,et al.  KIF5B and KIF3A/KIF3B kinesins drive MT1-MMP surface exposure, CD44 shedding, and extracellular matrix degradation in primary macrophages. , 2010, Blood.

[14]  D. Hommes,et al.  Impaired autophagy leads to abnormal dendritic cell-epithelial cell interactions. , 2013, Journal of Crohn's & colitis.

[15]  M. Yáñez-Mó,et al.  Membrane type 1-matrix metalloproteinase is involved in migration of human monocytes and is regulated through their interaction with fibronectin or endothelium. , 2005, Blood.

[16]  R. Díez-Ahedo,et al.  Geometry sensing by dendritic cells dictates spatial organization and PGE2-induced dissolution of podosomes , 2011, Cellular and Molecular Life Sciences.

[17]  N. Carragher,et al.  Inhibition of calpain stabilises podosomes and impairs dendritic cell motility , 2006, Journal of Cell Science.

[18]  Dunn,et al.  Chemotaxis of macrophages is abolished in the Wiskott‐Aldrich syndrome , 1998, British journal of haematology.

[19]  Mario Gimona,et al.  Assembly and biological role of podosomes and invadopodia. , 2008, Current opinion in cell biology.

[20]  L. Machesky,et al.  Podosomes in adhesion, migration, mechanosensing and matrix remodeling , 2013, Cytoskeleton.

[21]  Jason M. Byars,et al.  Dual-color superresolution microscopy reveals nanoscale organization of mechanosensory podosomes , 2013, Molecular biology of the cell.

[22]  S. Linder,et al.  Degrading devices: invadosomes in proteolytic cell invasion. , 2011, Annual review of cell and developmental biology.

[23]  Bihui Huang,et al.  Mucus Enhances Gut Homeostasis and Oral Tolerance by Delivering Immunoregulatory Signals , 2013, Science.

[24]  S. Akira,et al.  Toll-like receptors in innate immunity. , 2004, International immunology.

[25]  S. Lira,et al.  Luminal bacteria recruit CD103+ dendritic cells into the intestinal epithelium to sample bacterial antigens for presentation. , 2013, Immunity.

[26]  Dylan T Burnette,et al.  Bayesian localisation microscopy reveals nanoscale podosome dynamics , 2011, Nature Methods.

[27]  S. Watson,et al.  Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane. , 2013, Blood.

[28]  S. Courtneidge,et al.  The 'ins' and 'outs' of podosomes and invadopodia: characteristics, formation and function , 2011, Nature Reviews Molecular Cell Biology.

[29]  P. Ricciardi-Castagnoli,et al.  Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria , 2001, Nature Immunology.

[30]  Mary F Lipscomb,et al.  Dendritic cells: immune regulators in health and disease. , 2002, Physiological reviews.

[31]  Steffen Jung,et al.  Transepithelial Pathogen Uptake into the Small Intestinal Lamina Propria1 , 2006, The Journal of Immunology.

[32]  A. Prescott,et al.  Dendritic cell podosomes are protrusive and invade the extracellular matrix using metalloproteinase MMP-14 , 2010, Journal of Cell Science.

[33]  Hidde L Ploegh,et al.  CX3CR1-Mediated Dendritic Cell Access to the Intestinal Lumen and Bacterial Clearance , 2005, Science.

[34]  Z. Kouchi,et al.  Phosphatidylinositol 4,5‐bisphosphate and PIP5‐kinase Iα are required for invadopodia formation in human breast cancer cells , 2010, Cancer science.

[35]  D. Vestweber Novel insights into leukocyte extravasation , 2012, Current opinion in hematology.

[36]  M. Aepfelbacher,et al.  Wiskott-Aldrich syndrome protein regulates podosomes in primary human macrophages. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[37]  C. Figdor,et al.  Phenotypical and Functional Characterization of Clinical Grade Dendritic Cells , 2002, Journal of immunotherapy.

[38]  C. Carman,et al.  Antigen Recognition Is Facilitated by Invadosome-like Protrusions Formed by Memory/Effector T Cells , 2012, The Journal of Immunology.

[39]  V. Quaranta,et al.  Purification of immunologically functional subsets of human Ia-like antigens on a monoclonal antibody (Q5/13) immunoadsorbent. , 1980, Journal of immunology.

[40]  Robert M. Hoffman,et al.  Physical limits of cell migration: Control by ECM space and nuclear deformation and tuning by proteolysis and traction force , 2013, The Journal of cell biology.

[41]  R. Steinman,et al.  Dendritic cells and the control of immunity , 1998, Nature.

[42]  G. E. Jones,et al.  Configuration of human dendritic cell cytoskeleton by Rho GTPases, the WAS protein, and differentiation. , 2001, Blood.

[43]  Raphael Ruppert,et al.  Kindlin-3–mediated signaling from multiple integrin classes is required for osteoclast-mediated bone resorption , 2011, The Journal of cell biology.

[44]  Peter Friedl,et al.  Mapping proteolytic cancer cell-extracellular matrix interfaces , 2009, Clinical & Experimental Metastasis.

[45]  R. Fässler,et al.  The integrin–actin connection, an eternal love affair , 2003, The EMBO journal.

[46]  Ning Wang,et al.  Self-Organized Podosomes Are Dynamic Mechanosensors , 2008, Current Biology.

[47]  C. Figdor,et al.  Interplay between myosin IIA-mediated contractility and actin network integrity orchestrates podosome composition and oscillations , 2013, Nature Communications.

[48]  C. Figdor,et al.  A Critical Role for Prostaglandin E2 in Podosome Dissolution and Induction of High-Speed Migration during Dendritic Cell Maturation1 , 2006, The Journal of Immunology.

[49]  W. Abou-Kheir,et al.  Regulation of podosome dynamics by WASp phosphorylation: implication in matrix degradation and chemotaxis in macrophages , 2009, Journal of Cell Science.

[50]  M. Kirschner,et al.  Chemical inhibition of N-WASP by stabilization of a native autoinhibited conformation , 2004, Nature Structural &Molecular Biology.

[51]  S. Linder The matrix corroded: podosomes and invadopodia in extracellular matrix degradation. , 2007, Trends in cell biology.

[52]  R. Locksley,et al.  Spatiotemporally separated antigen uptake by alveolar dendritic cells and airway presentation to T cells in the lung , 2012, The Journal of experimental medicine.

[53]  A. Prescott,et al.  TLR ligand–induced podosome disassembly in dendritic cells is ADAM17 dependent , 2008, The Journal of cell biology.

[54]  O. Shupliakov,et al.  Role of the Clathrin Terminal Domain in Regulating Coated Pit Dynamics Revealed by Small Molecule Inhibition , 2011, Cell.

[55]  J. Reynolds,et al.  Extracellular Matrix Degradation , 2003, Definitions.

[56]  W. Lim,et al.  Integration of multiple signals through cooperative regulation of the N-WASP-Arp2/3 complex. , 2000, Science.

[57]  H. Grey,et al.  Antigen recognition by H-2-restricted T cells. I. Cell-free antigen processing , 1983, The Journal of experimental medicine.

[58]  R. Germain,et al.  Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement , 2006, The Journal of experimental medicine.

[59]  G. Dunn,et al.  Restoration of podosomes and chemotaxis in Wiskott-Aldrich syndrome macrophages following induced expression of WASp. , 2002, The international journal of biochemistry & cell biology.

[60]  C. Vieu,et al.  Dynamics of podosome stiffness revealed by atomic force microscopy , 2010, Proceedings of the National Academy of Sciences.

[61]  T. Rudel,et al.  The kinesin KIF9 and reggie/flotillin proteins regulate matrix degradation by macrophage podosomes , 2011, Molecular biology of the cell.

[62]  Steven Shapiro,et al.  Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP , 2004, The Journal of cell biology.

[63]  Douglas S Kwon,et al.  DC-SIGN, a Dendritic Cell–Specific HIV-1-Binding Protein that Enhances trans-Infection of T Cells , 2000, Cell.

[64]  R. Geha,et al.  Transcellular diapedesis is initiated by invasive podosomes. , 2007, Immunity.

[65]  N. Cole,et al.  Pitstop 2 Is a Potent Inhibitor of Clathrin-Independent Endocytosis , 2012, PloS one.

[66]  C. Figdor,et al.  Phenotypical and functional characterization of clinical-grade dendritic cells. , 2005, Methods in molecular medicine.