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Fucose-specific DC-SIGN signalling directs T helper cell type-2 responses via IKKε- and CYLD-dependent Bcl3 activation

Author

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  • Sonja I. Gringhuis

    (Academic Medical Center, University of Amsterdam)

  • Tanja M. Kaptein

    (Academic Medical Center, University of Amsterdam)

  • Brigitte A. Wevers

    (Academic Medical Center, University of Amsterdam)

  • Annelies W. Mesman

    (Academic Medical Center, University of Amsterdam)

  • Teunis B. H. Geijtenbeek

    (Academic Medical Center, University of Amsterdam)

Abstract

Carbohydrate-specific signalling through DC-SIGN provides dendritic cells with plasticity to tailor immunity to the nature of invading microbes. Here we demonstrate that recognition of fucose-expressing extracellular pathogens like Schistosoma mansoni and Helicobacter pylori by DC-SIGN favors T helper cell type-2 (TH2) responses via activation of atypical NF-κB family member Bcl3. Crosstalk between TLR and DC-SIGN signalling results in TLR-induced MK2-mediated phosphorylation of LSP1, associated with DC-SIGN, upon fucose binding. Subsequently, IKKε and CYLD are recruited to phosphorylated LSP1. IKKε activation is pivotal for suppression of CYLD deubiquitinase activity and subsequent nuclear translocation of ubiquitinated Bcl3. Bcl3 activation represses TLR-induced proinflammatory cytokine expression, while enhancing interleukin-10 (IL-10) and TH2-attracting chemokine expression, shifting TH differentiation from TH1 to TH2 polarization. Thus, DC-SIGN directs adaptive TH2 immunity to fucose-expressing pathogens via an IKKε-CYLD-dependent signalling pathway leading to Bcl3 activation, which might be targeted in vaccination strategies or to prevent aberrant inflammation and allergy.

Suggested Citation

  • Sonja I. Gringhuis & Tanja M. Kaptein & Brigitte A. Wevers & Annelies W. Mesman & Teunis B. H. Geijtenbeek, 2014. "Fucose-specific DC-SIGN signalling directs T helper cell type-2 responses via IKKε- and CYLD-dependent Bcl3 activation," Nature Communications, Nature, vol. 5(1), pages 1-13, September.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4898
    DOI: 10.1038/ncomms4898
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