Abstract
Cooperation between different innate signaling pathways induced by pattern-recognition receptors (PRRs) on dendritic cells (DCs) is crucial for tailoring adaptive immunity to pathogens. Here we show that carbohydrate-specific signaling through the C-type lectin DC-SIGN tailored cytokine production in response to distinct pathogens. DC-SIGN was constitutively associated with a signalosome complex consisting of the scaffold proteins LSP1, KSR1 and CNK and the kinase Raf-1. Mannose-expressing Mycobacterium tuberculosis and human immunodeficiency virus type 1 (HIV-1) induced the recruitment of effector proteins to the DC-SIGN signalosome to activate Raf-1, whereas fucose-expressing pathogens such as Helicobacter pylori actively dissociated the KSR1-CNK-Raf-1 complex from the DC-SIGN signalosome. This dynamic regulation of the signalosome by mannose- and fucose-expressing pathogens led to the enhancement or suppression of proinflammatory responses, respectively. Our study reveals another level of plasticity in tailoring adaptive immunity to pathogens.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Blotting, Western
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Carbohydrates / immunology*
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Cell Adhesion Molecules / immunology*
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Cell Adhesion Molecules / metabolism
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Cytokines / biosynthesis
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Cytokines / immunology
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Enzyme-Linked Immunosorbent Assay
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Flow Cytometry
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Fucose / immunology
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HIV-1 / immunology*
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Helicobacter pylori / immunology*
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Humans
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Lectins, C-Type / immunology*
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Lectins, C-Type / metabolism
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Mannose / immunology
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Microfilament Proteins / immunology
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Microfilament Proteins / metabolism
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Mycobacterium tuberculosis / immunology*
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Protein Kinases / immunology
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Protein Kinases / metabolism
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Proto-Oncogene Proteins c-raf / immunology
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Proto-Oncogene Proteins c-raf / metabolism
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Receptors, Cell Surface / immunology*
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Receptors, Cell Surface / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / immunology*
Substances
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Carbohydrates
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Cell Adhesion Molecules
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Cytokines
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DC-specific ICAM-3 grabbing nonintegrin
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LSP1 protein, human
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Lectins, C-Type
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Microfilament Proteins
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Receptors, Cell Surface
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Fucose
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Protein Kinases
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KSR-1 protein kinase
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Proto-Oncogene Proteins c-raf
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Mannose