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PMID: 12515809 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Mycobacteria target DC-SIGN to suppress dendritic cell function.

The Journal of experimental medicine ·Vol. 197 ·No. 1 ·2003-01-06 ·Pages 7-17

Geijtenbeek TB, Van Vliet SJ, Koppel EA, Sanchez-Hernandez M, Vandenbroucke-Grauls CM, Appelmelk B, Van Kooyk Y

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.

MeSH Terms
Bacterial Adhesion Binding Sites Cell Adhesion Molecules/chemistry,metabolism Cell Division Cells, Cultured Dendritic Cells/immunology,metabolism,microbiology Drosophila Proteins Endocytosis Glycolipids/metabolism Humans Immune Tolerance Interleukin-10/metabolism Lectins, C-Type/chemistry,metabolism Lipopolysaccharides/metabolism Lysosomes/metabolism Membrane Glycoproteins/metabolism Mycobacterium tuberculosis/metabolism Protein Binding Receptors, Cell Surface/chemistry,metabolism Signal Transduction Toll-Like Receptors
Chemicals
Cell Adhesion Molecules DC-specific ICAM-3 grabbing nonintegrin Drosophila Proteins Glycolipids Lectins, C-Type Lipopolysaccharides Membrane Glycoproteins Receptors, Cell Surface Toll-Like Receptors lipoarabinomannan Interleukin-10
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Geijtenbeek Teunis B H
Department of Molecular Cell Biology, Vrije Universiteit Medical Center Amsterdam, 1081 BT Amsterdam, Netherlands. [email protected]
Van Vliet Sandra J
Koppel Estella A
Sanchez-Hernandez Marta
Vandenbroucke-Grauls Christine M J E
Appelmelk Ben
Van Kooyk Yvette
References (41)
41 references, click to expand
  1. Immune escape through C-type lectins on dendritic cells.
    Trends Immunol. 2002 Oct;23(10):480-5 PMID: 12297419
  2. Identification of different binding sites in the dendritic cell-specific receptor DC-SIGN for intercellular adhesion molecule 3 and HIV-1.
    J Biol Chem. 2002 Mar 29;277(13):11314-20 PMID: 11799126
  3. Biochemical and functional characteristics of the human leukocyte membrane antigen family LFA-1, Mo-1 and p150,95.
    Eur J Immunol. 1985 Nov;15(11):1142-8 PMID: 2933266
  4. The use of fluorescence quenching in flow cytofluorometry to measure the attachment and ingestion phases in phagocytosis in peripheral blood without prior cell separation.
    J Immunol Methods. 1987 Jul 16;101(1):119-25 PMID: 3112235
  5. Evaluation of lipoarabinomannan for the serological diagnosis of tuberculosis.
    J Clin Microbiol. 1990 Dec;28(12):2587-90 PMID: 2126265
  6. Macrophage phagocytosis of virulent but not attenuated strains of Mycobacterium tuberculosis is mediated by mannose receptors in addition to complement receptors.
    J Immunol. 1993 Apr 1;150(7):2920-30 PMID: 8454864
  7. Dendritic cell progenitors phagocytose particulates, including bacillus Calmette-Guerin organisms, and sensitize mice to mycobacterial antigens in vivo.
    J Exp Med. 1993 Aug 1;178(2):479-88 PMID: 7688024
  8. Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase.
    Science. 1994 Feb 4;263(5147):678-81 PMID: 8303277
  9. Binding of the terminal mannosyl units of lipoarabinomannan from a virulent strain of Mycobacterium tuberculosis to human macrophages.
    J Immunol. 1994 Apr 15;152(8):4070-9 PMID: 8144972
  10. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha.
    J Exp Med. 1994 Apr 1;179(4):1109-18 PMID: 8145033
  11. Intracellular trafficking in Mycobacterium tuberculosis and Mycobacterium avium-infected macrophages.
    J Immunol. 1994 Sep 15;153(6):2568-78 PMID: 8077667
  12. Immunopathology of tuberculosis: roles of macrophages and monocytes.
    Infect Immun. 1996 Mar;64(3):683-90 PMID: 8641767
  13. The mannose receptor delivers lipoglycan antigens to endosomes for presentation to T cells by CD1b molecules.
    Immunity. 1997 Feb;6(2):187-97 PMID: 9047240
  14. Activation of human dendritic cells following infection with Mycobacterium tuberculosis.
    J Immunol. 1997 Jul 15;159(2):635-43 PMID: 9218578
  15. Mycobacterial lipoarabinomannan: an extraordinary lipoheteroglycan with profound physiological effects.
    Glycobiology. 1998 Feb;8(2):113-20 PMID: 9451020
  16. Dendritic cells and the control of immunity.
    Nature. 1998 Mar 19;392(6673):245-52 PMID: 9521319
  17. Interactions between Mycobacterium tuberculosis and host cells: are mycobacterial sugars the key?
    Trends Microbiol. 1998 Aug;6(8):328-35 PMID: 9746944
  18. Interleukin-10-treated human dendritic cells induce a melanoma-antigen-specific anergy in CD8(+) T cells resulting in a failure to lyse tumor cells.
    Blood. 1999 Mar 1;93(5):1634-42 PMID: 10029592
  19. Protection against aerosol Mycobacterium tuberculosis infection using Mycobacterium bovis Bacillus Calmette Guérin-infected dendritic cells.
    Eur J Immunol. 1999 Jun;29(6):1972-9 PMID: 10382760
  20. High frequency of adhesion defects in B-lineage acute lymphoblastic leukemia.
    Blood. 1999 Jul 15;94(2):754-64 PMID: 10397743
  21. Enhanced antigen-presenting activity and tumour necrosis factor-alpha-independent activation of dendritic cells following treatment with Mycobacterium bovis bacillus Calmette-Guérin.
    Immunology. 1999 Aug;97(4):626-33 PMID: 10457216
  22. Defining the requirements for immunological control of mycobacterial infections.
    Trends Microbiol. 1999 Sep;7(9):366-72 PMID: 10470045
  23. Phorbol ester induces abnormal chronic lymphocytic leukemia cells to express features of hairy cell leukemia.
    Blood. 1985 Nov;66(5):1035-42 PMID: 3876853
  24. Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses.
    Cell. 2000 Mar 3;100(5):575-85 PMID: 10721994
  25. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells.
    Cell. 2000 Mar 3;100(5):587-97 PMID: 10721995
  26. Interaction of dendritic cells with mycobacteria: where the action starts.
    Immunol Cell Biol. 2000 Aug;78(4):318-24 PMID: 10947855
  27. Is the development of a new tuberculosis vaccine possible?
    Nat Med. 2000 Sep;6(9):955-60 PMID: 10973302
  28. Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells.
    J Exp Med. 2000 Nov 6;192(9):1213-22 PMID: 11067871
  29. Maturation of human dendritic cells by cell wall skeleton of Mycobacterium bovis bacillus Calmette-Guérin: involvement of toll-like receptors.
    Infect Immun. 2000 Dec;68(12):6883-90 PMID: 11083809
  30. Latent Mycobacterium tuberculosis-persistence, patience, and winning by waiting.
    Nat Med. 2000 Dec;6(12):1327-9 PMID: 11100115
  31. Characterization of murine lung dendritic cells infected with Mycobacterium tuberculosis.
    Infect Immun. 2001 Feb;69(2):1127-33 PMID: 11160010
  32. Hijacking and exploitation of IL-10 by intracellular pathogens.
    Trends Microbiol. 2001 Feb;9(2):86-92 PMID: 11173248
  33. Mannosylated lipoarabinomannans inhibit IL-12 production by human dendritic cells: evidence for a negative signal delivered through the mannose receptor.
    J Immunol. 2001 Jun 15;166(12):7477-85 PMID: 11390501
  34. A novel mechanism of carbohydrate recognition by the C-type lectins DC-SIGN and DC-SIGNR. Subunit organization and binding to multivalent ligands.
    J Biol Chem. 2001 Aug 3;276(31):28939-45 PMID: 11384997
  35. Toll-like receptors: critical proteins linking innate and acquired immunity.
    Nat Immunol. 2001 Aug;2(8):675-80 PMID: 11477402
  36. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens.
    J Exp Med. 2001 Sep 17;194(6):863-9 PMID: 11561001
  37. Structural basis for selective recognition of oligosaccharides by DC-SIGN and DC-SIGNR.
    Science. 2001 Dec 7;294(5549):2163-6 PMID: 11739956
  38. Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells.
    Eur J Immunol. 2001 Nov;31(11):3388-93 PMID: 11745357
  39. Dendritic cells are host cells for mycobacteria in vivo that trigger innate and acquired immunity.
    J Immunol. 2002 Feb 1;168(3):1294-301 PMID: 11801668
  40. The dendritic cell-specific adhesion receptor DC-SIGN internalizes antigen for presentation to T cells.
    J Immunol. 2002 Mar 1;168(5):2118-26 PMID: 11859097
  41. C-type lectin receptors on dendritic cells and Langerhans cells.
    Nat Rev Immunol. 2002 Feb;2(2):77-84 PMID: 11910898
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20021229
Email
[email protected]
Published
2003-01-06
Pages
7-17
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2193797
Subset
IM
Corrections
CommentIn
PMID: 12515808
External Links
PubMed source DOI: 10.1084/jem.20021229 PMC Full Text View journal details
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