Abstract
Follicular helper T (Tfh) cells have a central role in mediating humoral immune responses. Generation of Tfh cells depends on both T-cell intrinsic factors and the supporting function of B cells, but the underlying molecular mechanisms are incompletely understood. Here we show that NF-κB-inducing kinase (NIK), a central component of the noncanonical NF-κB signaling pathway, is required for Tfh cell development. Unlike other known Tfh regulators, NIK acts by controlling the supporting function of B cells. NIK and its upstream BAFF receptor regulate B-cell expression of inducible costimulator ligand (ICOSL), a molecule required for Tfh cell generation. Consistently, injection of a recombinant ICOSL protein into NIK-deficient mice largely rescues their defect in Tfh cell development. We provide biochemical and genetic evidence indicating that the ICOSL gene is a specific target of the noncanonical NF-κB. Our findings suggest that the noncanonical NF-κB pathway regulates the development of Tfh cells by mediating ICOSL gene expression in B cells.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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B-Cell Activation Factor Receptor / genetics
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B-Cell Activation Factor Receptor / immunology
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B-Cell Activation Factor Receptor / metabolism
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B-Lymphocytes / drug effects
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B-Lymphocytes / immunology
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B-Lymphocytes / metabolism
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Base Sequence
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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Cell Differentiation / immunology
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Female
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Flow Cytometry
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Gene Expression
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HEK293 Cells
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Humans
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Immunization / methods
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Inducible T-Cell Co-Stimulator Ligand
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Leukocyte Common Antigens / immunology
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Leukocyte Common Antigens / metabolism
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Lipopolysaccharides / pharmacology
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Male
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Mice
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Mice, 129 Strain
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Mice, Knockout
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NF-kappa B / genetics
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NF-kappa B / immunology*
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NF-kappa B / metabolism
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NF-kappaB-Inducing Kinase
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Promoter Regions, Genetic / genetics
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Protein Binding
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / immunology*
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Protein Serine-Threonine Kinases / metabolism
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Proteins / genetics
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Proteins / immunology*
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Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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T-Lymphocytes, Helper-Inducer / immunology*
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T-Lymphocytes, Helper-Inducer / metabolism
Substances
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B-Cell Activation Factor Receptor
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Icosl protein, mouse
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Inducible T-Cell Co-Stimulator Ligand
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Lipopolysaccharides
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NF-kappa B
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Proteins
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Tnfrsf13c protein, mouse
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Protein Serine-Threonine Kinases
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Leukocyte Common Antigens