title: B-cell survival and development controlled by the coordination of NF-κB family members RelB and cRel.
abstract: Targeted deletion of BAFF causes severe deficiency of splenic B cells. BAFF-R is commonly thought to signal to nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase dependent noncanonical NF-κB RelB. However, RelB-deficient mice have normal B-cell numbers. Recent studies showed that BAFF also signals to the canonical NF-κB pathway, and we found that both RelB and cRel are persistently activated, suggesting BAFF signaling coordinates both pathways to ensure robust B-cell development. Indeed, we report now that combined loss of these 2 NF-κB family members leads to impaired BAFF-mediated survival and development in vitro. Although single deletion of RelB and cRel was dispensable for normal B-cell development, double knockout mice displayed an early B-cell developmental blockade and decreased mature B cells. Despite disorganized splenic architecture in Relb(-/-)cRel(-/-) mice, generation of mixed-mouse chimeras established the developmental phenotype to be B-cell intrinsic. Together, our results indicate that BAFF signals coordinate both RelB and cRel activities to ensure survival during peripheral B-cell maturation.
authors.affiliation: Signaling Systems Laboratory and San Diego Center for Systems Biology, University of California, San Diego, La Jolla, CA;
authors.forename: Jonathan V
authors.initials: JV
authors.lastname: Almaden
authors.affiliation: Signaling Systems Laboratory and San Diego Center for Systems Biology, University of California, San Diego, La Jolla, CA; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA;
authors.forename: Yi C
authors.identifier: http://orcid.org/0000-0003-1372-2101
authors.initials: YC
authors.lastname: Liu
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA; and.
authors.forename: Edward
authors.initials: E
authors.lastname: Yang
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA; and.
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Otero
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA;
authors.forename: Harry
authors.initials: H
authors.lastname: Birnbaum
authors.affiliation: Signaling Systems Laboratory and San Diego Center for Systems Biology, University of California, San Diego, La Jolla, CA;
authors.forename: Jeremy
authors.initials: J
authors.lastname: Davis-Turak
authors.affiliation: Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Asagiri
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA; and.
authors.forename: Michael
authors.initials: M
authors.lastname: David
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA; and.
authors.forename: Ananda W
authors.initials: AW
authors.lastname: Goldrath
authors.affiliation: Signaling Systems Laboratory and San Diego Center for Systems Biology, University of California, San Diego, La Jolla, CA; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA;
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
mesh_terms: D000818:Animals; D053264:B-Cell Activating Factor / Q000235:genetics / Q000378:metabolism; D053265:B-Cell Activation Factor Receptor / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051841:Transcription Factor RelB / Q000235:genetics / Q000378:metabolism*
chemical_list: D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; C497594:Relb protein, mouse; C486662:Tnfrsf13c protein, mouse; C505720:Tnfsf13b protein, mouse; D051841:Transcription Factor RelB; D051096:Proto-Oncogene Proteins c-ret