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Carbohydrate-specific signaling through the DC-SIGN signalosome tailors immunity to Mycobacterium tuberculosis, HIV-1 and Helicobacter pylori

Nature Immunology volume 10, pages 1081–1088 (2009)Cite this article

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.

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Figure 1: Raf-1 activation is central to mannose-dependent but not fucose-dependent DC-SIGN-mediated modulation of TLR4-induced cytokine production.
Figure 2: Mannose-specific DC-SIGN signaling requires LSP1.
Figure 3: Mannose-specific DC-SIGN signaling requires a signalosome consisting of LSP1 and the KSR1–CNK–Raf-1 triad complex.
Figure 4: Mannose-specific triggering of DC-SIGN recruits LARG and RhoA to the signalosome, which is essential for Raf-1 activation via Ras.
Figure 5: Fucose-specific DC-SIGN triggering dissociates KSR1–CNK–Raf-1 but not LSP1 from the signalosome.
Figure 6: Carbohydrate-specific DC-SIGN signaling leads to pathogen-specific cytokine responses.

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Acknowledgements

ManLAM and M. tuberculosis were gifts from J. Belisle (Colorado State University; as part of the National Institute of Allergy and Infectious Diseases, US National Institutes of Health contract HHSN266200400091C, “Tuberculosis Vaccine Testing and Research Materials”); H. pylori strains were gifts from B. Appelmelk (Vrije University Medical Center); and ICAM-3–Fc was a gift from D. Simmons (University of Oxford). Supported by the Dutch Scientific Research Program (NWO 912-04-025 to J.d.D.), the AIDS Foundation (2007036 to M.d.v.V.) and the Dutch Asthma Foundation (3.2.03.39 to S.I.G.).

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Author notes

  1. Jeroen den Dunnen

    Present address: Present address: Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.,

  2. Jeroen den Dunnen and Manja Litjens: These authors contributed equally to this work.

Authors and Affiliations

  1. Center of Infection and Immunity Amsterdam and Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Sonja I Gringhuis, Michiel van der Vlist & Teunis B H Geijtenbeek

  2. Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands

    Sonja I Gringhuis, Jeroen den Dunnen, Manja Litjens, Michiel van der Vlist & Teunis B H Geijtenbeek

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Contributions

S.I.G. designed, did and interpreted most experiments and prepared the manuscript; J.d.D. and M.L. participated in RNAi, flow cytometry and immunoblot experiments; M.v.d.V. assisted with flow cytometry and Ras-precipitation experiments; and T.B.H.G. participated in flow cytometry and enzyme-linked immunosorbent assays (ELISAs) and supervised all aspects of this study.

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Correspondence to Sonja I Gringhuis or Teunis B H Geijtenbeek.

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Gringhuis, S., den Dunnen, J., Litjens, M. et al. Carbohydrate-specific signaling through the DC-SIGN signalosome tailors immunity to Mycobacterium tuberculosis, HIV-1 and Helicobacter pylori. Nat Immunol 10, 1081–1088 (2009). https://doi.org/10.1038/ni.1778

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