title: Mycobacteria target DC-SIGN to suppress dendritic cell function.
abstract: Mycobacterium tuberculosis represents a world-wide health risk and immunosuppression is a particular problem in M. tuberculosis infections. Although macrophages are primarily infected, dendritic cells (DCs) are important in inducing cellular immune responses against M. tuberculosis. We hypothesized that DCs represent a target for M. tuberculosis and that the observed immuno-suppression results from modulation of DC functions. We demonstrate that the DC-specific C-type lectin DC-SIGN is an important receptor on DCs that captures and internalizes intact Mycobacterium bovis bacillus Calmette-Guérin (BCG) through the mycobacterial cell wall component ManLAM. Antibodies against DC-SIGN block M. bovis BCG infection of DCs. ManLAM is also secreted by M. tuberculosis-infected macrophages and has been implicated as a virulence factor. Strikingly, ManLAM binding to DC-SIGN prevents mycobacteria- or LPS-induced DC maturation. Both mycobacteria and LPS induce DC maturation through Toll-like receptor (TLR) signaling, suggesting that DC-SIGN, upon binding of ManLAM, interferes with TLR-mediated signals. Blocking antibodies against DC-SIGN reverse the ManLAM-mediated immunosuppressive effects. Our results suggest that M. tuberculosis targets DC-SIGN both to infect DCs and to down-regulate DC-mediated immune responses. Moreover, we demonstrate that DC-SIGN has a broader pathogen recognition profile than previously shown, suggesting that DC-SIGN may represent a molecular target for clinical intervention in infections other than HIV-1.
authors.affiliation: Department of Molecular Cell Biology, Vrije Universiteit Medical Center Amsterdam, 1081 BT Amsterdam, Netherlands. T.Geijtenbeek.Cell@med.vu.nl
authors.forename: Teunis B H
authors.initials: TB
authors.lastname: Geijtenbeek
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Van Vliet
authors.forename: Estella A
authors.initials: EA
authors.lastname: Koppel
authors.forename: Marta
authors.initials: M
authors.lastname: Sanchez-Hernandez
authors.forename: Christine M J E
authors.initials: CM
authors.lastname: Vandenbroucke-Grauls
authors.forename: Ben
authors.initials: B
authors.lastname: Appelmelk
authors.forename: Yvette
authors.initials: Y
authors.lastname: Van Kooyk
mesh_terms: D001422:Bacterial Adhesion; D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism*; D002455:Cell Division; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D029721:Drosophila Proteins; D004705:Endocytosis; D006017:Glycolipids / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000378:metabolism; D037181:Lectins, C-Type / Q000737:chemistry / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D029721:Drosophila Proteins; D006017:Glycolipids; D016753:Interleukin-10; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C050016:lipoarabinomannan