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

Sonja I. Gringhuis; Tanja M. Kaptein; Brigitte A. Wevers; Annelies W. Mesman; Teunis B. H. Geijtenbeek

doi:https://doi.org/10.1038/ncomms4898

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

Sonja I. Gringhuis, Tanja M. Kaptein, Brigitte A. Wevers, Annelies W. Mesman, Teunis B. H. Geijtenbeek

Research output: Contribution to journal › Article › Academic › peer-review

116 Citations (Scopus)

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

Original language	English
Pages (from-to)	3898
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms4898
Publication status	Published - 2014

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https://doi.org/10.1038/ncomms4898

Cite this

@article{61b6f9cb170d4b95ba48922176abdb90,

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

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",

author = "Gringhuis, {Sonja I.} and Kaptein, {Tanja M.} and Wevers, {Brigitte A.} and Mesman, {Annelies W.} and Geijtenbeek, {Teunis B. H.}",

year = "2014",

doi = "https://doi.org/10.1038/ncomms4898",

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volume = "5",

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journal = "Nature communications",

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T1 - Fucose-specific DC-SIGN signalling directs T helper cell type-2 responses via IKKε- and CYLD-dependent Bcl3 activation

AU - Gringhuis, Sonja I.

AU - Kaptein, Tanja M.

AU - Wevers, Brigitte A.

AU - Mesman, Annelies W.

AU - Geijtenbeek, Teunis B. H.

PY - 2014

Y1 - 2014

N2 - 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

AB - 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

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