title: Noncanonical NF-kappaB regulates inducible costimulator (ICOS) ligand expression and T follicular helper cell development.
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.
authors.affiliation: Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Hu
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wu
authors.forename: Wei
authors.initials: W
authors.lastname: Jin
authors.forename: Mikyoung
authors.initials: M
authors.lastname: Chang
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cheng
authors.forename: Shao-Cong
authors.initials: SC
authors.lastname: Sun
mesh_terms: D000818:Animals; D053265:B-Cell Activation Factor Receptor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D007114:Immunization / Q000379:methods; D060945:Inducible T-Cell Co-Stimulator Ligand; D017493:Leukocyte Common Antigens / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D053265:B-Cell Activation Factor Receptor; D060945:Inducible T-Cell Co-Stimulator Ligand; D017493:Leukocyte Common Antigens; D008070:Lipopolysaccharides; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D000097782:NF-kappaB-Inducing Kinase; C400230:Icosl protein, mouse; C486662:Tnfrsf13c protein, mouse