Carbohydrate-specific signaling through the DC-SIGN signalosome tailors immunity to Mycobacterium tuberculosis, HIV-1 and Helicobacter pylori.
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.
Gringhuis
Sonja I
SI
Center of Infection and Immunity Amsterdam, University of Amsterdam, Amsterdam, The Netherlands. s.i.gringhuis@amc.uva.nl
den Dunnen
Jeroen
J
Litjens
Manja
M
van der Vlist
Michiel
M
Geijtenbeek
Teunis B H
TB
D015153:Blotting, Western; D002241:Carbohydrates / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005643:Fucose / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D016480:Helicobacter pylori / Q000276:immunology*; D006801:Humans; D037181:Lectins, C-Type / Q000276:immunology* / Q000378:metabolism; D008358:Mannose / Q000276:immunology; D008840:Microfilament Proteins / Q000276:immunology / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D011494:Protein Kinases / Q000276:immunology / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D002241:Carbohydrates; D015815:Cell Adhesion Molecules; D016207:Cytokines; D005643:Fucose; D037181:Lectins, C-Type; D008358:Mannose; D008840:Microfilament Proteins; D011494:Protein Kinases; D019908:Proto-Oncogene Proteins c-raf; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C489183:LSP1 protein, human; C097199:KSR-1 protein kinase