title: Differential requirements for the canonical NF-κB transcription factors c-REL and RELA during the generation and activation of mature B cells.
abstract: Signaling through the canonical nuclear factor-κB (NF-κB) pathway is critical for the generation and maintenance of mature B cells and for antigen-dependent B-cell activation. c-REL (rel) and RELA (rela) are the downstream transcriptional activators of the canonical NF-κB pathway. Studies of B cells derived from constitutional rel knockout mice and chimeric mice repopulated with rela-/-fetal liver cells provided evidence that the subunits can have distinct roles during B-cell development. However, the B cell-intrinsic functions of c-REL and RELA during B-cell generation and antigen-dependent B-cell activation have not been determined in vivo. To clarify this issue, we crossed mice with conditional rel and rela alleles individually or in combination to mice that express Cre-recombinase in B cells. We here report that, whereas single deletion of rel or rela did not impair mature B-cell generation and maintenance, their simultaneous deletion led to a dramatic reduction of follicular and marginal zone B cells. Upon T cell-dependent immunization, B cell-specific deletion of the c-REL subunit alone abrogated the formation of germinal centers (GCs), whereas rela deletion did not affect GC formation. T-independent responses were strongly impaired in mice with B cell-specific deletion of rel, and only modestly in mice with RELA-deficient B cells. Our findings identify differential requirements for the canonical NF-κB subunits c-REL and RELA at distinct stages of mature B-cell development. The subunits are jointly required for the generation of mature B cells. During antigen-dependent B-cell activation, c-REL is the critical subunit required for the initiation of the GC reaction and for optimal T-independent antibody responses, with RELA being largely dispensable at this stage.
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, U.S.A.
authors.forename: Maja
authors.initials: M
authors.lastname: Milanovic
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, U.S.A.
authors.forename: Nicole
authors.initials: N
authors.lastname: Heise
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, U.S.A.
authors.forename: Nilushi S
authors.initials: NS
authors.lastname: De Silva
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, U.S.A.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Anderson
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, U.S.A.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Silva
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, U.S.A.
authors.forename: Amanda
authors.initials: A
authors.lastname: Carette
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, U.S.A.
authors.forename: Fabiano
authors.initials: F
authors.lastname: Orelli
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, U.S.A.|Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, U.S.A.
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, U.S.A.|Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, U.S.A.|Department of Microbiology and Immunology, Columbia University, New York, NY 10032, U.S.A.
authors.forename: Ulf
authors.initials: U
authors.lastname: Klein
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D053264:B-Cell Activating Factor / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D002470:Cell Survival; D017353:Gene Deletion; D018858:Germinal Center / Q000166:cytology; D019426:Integrases / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D008810:Mice, Inbred C57BL; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism*; D013154:Spleen / Q000166:cytology; D051996:Transcription Factor RelA / Q000378:metabolism*
chemical_list: D053264:B-Cell Activating Factor; D020569:Proto-Oncogene Proteins c-rel; C505720:Tnfsf13b protein, mouse; D051996:Transcription Factor RelA; C045073:Cre recombinase; D019426:Integrases