Mycobacteria Target DC-SIGN to Suppress Dendritic Cell Function
Copyright policy )Mycobacteria Target DC-SIGN to Suppress Dendritic Cell Function
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.
- Vrije Universiteit Amsterdam Netherlands
- Amsterdam UMC Netherlands
- Amsterdam UMC, location VUmc Netherlands
Lipopolysaccharides, Cells, Receptors, Cell Surface, Lysosomes/metabolism, Article, Bacterial Adhesion, Interleukin-10/metabolism, Lectins, Mycobacterium tuberculosis/metabolism, Receptors, Immune Tolerance, Drosophila Proteins, Humans, Lectins, C-Type, Cells, Cultured, Cell Adhesion Molecules/chemistry, Cultured, Binding Sites, Membrane Glycoproteins, Toll-Like Receptors, Membrane Glycoproteins/metabolism, Dendritic Cells, Mycobacterium tuberculosis, Glycolipids/metabolism, Endocytosis, Interleukin-10, Dendritic Cells/immunology, Cell Surface/chemistry, Glycolipids, Lysosomes, Cell Adhesion Molecules, C-Type/chemistry, Lipopolysaccharides/metabolism, Cell Division, Protein Binding, Signal Transduction
Lipopolysaccharides, Cells, Receptors, Cell Surface, Lysosomes/metabolism, Article, Bacterial Adhesion, Interleukin-10/metabolism, Lectins, Mycobacterium tuberculosis/metabolism, Receptors, Immune Tolerance, Drosophila Proteins, Humans, Lectins, C-Type, Cells, Cultured, Cell Adhesion Molecules/chemistry, Cultured, Binding Sites, Membrane Glycoproteins, Toll-Like Receptors, Membrane Glycoproteins/metabolism, Dendritic Cells, Mycobacterium tuberculosis, Glycolipids/metabolism, Endocytosis, Interleukin-10, Dendritic Cells/immunology, Cell Surface/chemistry, Glycolipids, Lysosomes, Cell Adhesion Molecules, C-Type/chemistry, Lipopolysaccharides/metabolism, Cell Division, Protein Binding, Signal Transduction
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