Abstract
Dendritic cells (DCs) orchestrate antibody-mediated responses to combat extracellular pathogens including parasites by initiating T helper cell differentiation. Here we demonstrate that carbohydrate-specific signalling by DC-SIGN drives follicular T helper cell (TFH) differentiation via IL-27 expression. Fucose, but not mannose, engagement of DC-SIGN results in activation of IKKε, which collaborates with type I IFNR signalling to induce formation and activation of transcription factor ISGF3. Notably, ISGF3 induces expression of IL-27 subunit p28, and subsequent IL-27 secreted by DC-SIGN-primed DCs is pivotal for the induction of Bcl-6(+)CXCR5(+)PD-1(hi)Foxp1(lo) TFH cells, IL-21 secretion by TFH cells and T-cell-dependent IgG production by B cells. Thus, we have identified an essential role for DC-SIGN-induced ISGF3 by fucose-based PAMPs in driving IL-27 and subsequent TFH polarization, which might be harnessed for vaccination design.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Motifs
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B-Lymphocytes / cytology
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Cell Adhesion Molecules / metabolism*
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Cell Differentiation
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Cell Nucleus / metabolism
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DNA-Binding Proteins / metabolism
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Dendritic Cells / cytology*
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Dimerization
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Flow Cytometry
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Fucose / chemistry*
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Humans
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Immunoglobulin G / chemistry
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Interferon Regulatory Factor-7 / metabolism
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Interferon-Stimulated Gene Factor 3, gamma Subunit / metabolism*
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Interleukin-27 / metabolism*
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Lectins, C-Type / metabolism*
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Leukocytes, Mononuclear / cytology
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Lymphocyte Activation / immunology
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Mannose / chemistry
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Proto-Oncogene Proteins c-bcl-6
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RNA Interference
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Receptors, Cell Surface / metabolism*
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Signal Transduction
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T-Lymphocytes, Helper-Inducer / cytology*
Substances
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BCL6 protein, human
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Cell Adhesion Molecules
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DC-specific ICAM-3 grabbing nonintegrin
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DNA-Binding Proteins
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IRF7 protein, human
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IRF9 protein, human
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Immunoglobulin G
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Interferon Regulatory Factor-7
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Interferon-Stimulated Gene Factor 3, gamma Subunit
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Interleukin-27
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Lectins, C-Type
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Proto-Oncogene Proteins c-bcl-6
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Receptors, Cell Surface
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Fucose
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Mannose