title: IKK-induced NF-κB1 p105 proteolysis is critical for B cell antibody responses to T cell-dependent antigen.
abstract: The importance of IκB kinase (IKK)-induced proteolysis of NF-κB1 p105 in B cells was investigated using Nfkb1(SSAA/SSAA) mice, in which this NF-κB signaling pathway is blocked. Nfkb1(SSAA) mutation had no effect on the development and homeostasis of follicular mature (FM) B cells. However, analysis of mixed bone marrow chimeras revealed that Nfkb1(SSAA/SSAA) FM B cells were completely unable to mediate T cell-dependent antibody responses. Nfkb1(SSAA) mutation decreased B cell antigen receptor (BCR) activation of NF-κB in FM B cells, which selectively blocked BCR stimulation of cell survival and antigen-induced differentiation into plasmablasts and germinal center B cells due to reduced expression of Bcl-2 family proteins and IRF4, respectively. In contrast, the antigen-presenting function of FM B cells and their BCR-induced migration to the follicle T cell zone border, as well as their growth and proliferation after BCR stimulation, were not affected. All of the inhibitory effects of Nfkb1(SSAA) mutation on B cell functions were rescued by normalizing NF-κB activation genetically. Our study identifies critical B cell-intrinsic functions for IKK-induced NF-κB1 p105 proteolysis in the antigen-induced survival and differentiation of FM B cells, which are essential for T-dependent antibody responses.
authors.affiliation: Division of Immune Cell Biology, MRC National Institute for Medical Research, London NW7 1AA, England, UK.
authors.forename: Emilie
authors.initials: E
authors.lastname: Jacque
authors.affiliation: Division of Immune Cell Biology, MRC National Institute for Medical Research, London NW7 1AA, England, UK.
authors.forename: Edina
authors.initials: E
authors.lastname: Schweighoffer
authors.affiliation: Division of Immune Cell Biology, MRC National Institute for Medical Research, London NW7 1AA, England, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Visekruna
authors.affiliation: Division of Immune Cell Biology, MRC National Institute for Medical Research, London NW7 1AA, England, UK.
authors.forename: Stamatia
authors.initials: S
authors.lastname: Papoutsopoulou
authors.affiliation: Division of Immune Cell Biology, MRC National Institute for Medical Research, London NW7 1AA, England, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Janzen
authors.affiliation: Division of Immune Cell Biology, MRC National Institute for Medical Research, London NW7 1AA, England, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Zillwood
authors.affiliation: The Walter and Eliza Hall Institute for Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Tarlinton
authors.affiliation: Division of Immune Cell Biology, MRC National Institute for Medical Research, London NW7 1AA, England, UK.
authors.forename: Victor L J
authors.initials: VL
authors.lastname: Tybulewicz
authors.affiliation: Division of Immune Cell Biology, MRC National Institute for Medical Research, London NW7 1AA, England, UK sley@nimr.mrc.ac.uk.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Ley
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D005434:Flow Cytometry; D051550:I-kappa B Kinase / Q000378:metabolism*; D015151:Immunoblotting; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009154:Mutation / Q000235:genetics; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D060888:Real-Time Polymerase Chain Reaction; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D052002:NF-kappa B p50 Subunit; D011947:Receptors, Antigen, B-Cell; D051550:I-kappa B Kinase