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.

Original languageEnglish
Pages (from-to)7-17
Number of pages11
JournalJournal of Experimental Medicine
Issue number1
Publication statusPublished - 6 Jan 2003


  • Bacterial Adhesion
  • Binding Sites
  • Cell Adhesion Molecules/chemistry
  • Cell Division
  • Cells, Cultured
  • Dendritic Cells/immunology
  • Drosophila Proteins
  • Endocytosis
  • Glycolipids/metabolism
  • Humans
  • Immune Tolerance
  • Interleukin-10/metabolism
  • Lectins, C-Type/chemistry
  • Lipopolysaccharides/metabolism
  • Lysosomes/metabolism
  • Membrane Glycoproteins/metabolism
  • Mycobacterium tuberculosis/metabolism
  • Protein Binding
  • Receptors, Cell Surface/chemistry
  • Signal Transduction
  • Toll-Like Receptors

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