title: Impairment of Mature B Cell Maintenance upon Combined Deletion of the Alternative NF-κB Transcription Factors RELB and NF-κB2 in B Cells.
abstract: BAFF is critical for the survival and maturation of mature B cells. BAFF, via BAFFR, activates multiple signaling pathways in B cells, including the alternative NF-κB pathway. The transcription factors RELB and NF-κB2 (p100/p52) are the downstream mediators of the alternative pathway; however, the B cell-intrinsic functions of these NF-κB subunits have not been studied in vivo using conditional alleles, either individually or in combination. We in this study report that B cell-specific deletion of relb led to only a slight decrease in the fraction of mature splenic B cells, whereas deletion of nfkb2 caused a marked reduction. This phenotype was further exacerbated upon combined deletion of relb and nfkb2 and most dramatically affected the maintenance of marginal zone B cells. BAFF stimulation, in contrast to CD40 activation, was unable to rescue relb/nfkb2-deleted B cells in vitro. RNA-sequencing analysis of BAFF-stimulated nfkb2-deleted versus normal B cells suggests that the alternative NF-κB pathway, in addition to its critical role in BAFF-mediated cell survival, may control the expression of genes involved in the positioning of B cells within the lymphoid microenvironment and in the establishment of T cell-B cell interactions. Thus, by ablating the downstream transcription factors of the alternative NF-κB pathway specifically in B cells, we identify in this study a critical role for the combined activity of the RELB and NF-κB2 subunits in B cell homeostasis that cannot be compensated for by the canonical NF-κB pathway under physiological conditions.
authors: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032; Department of Microbiology and Immunology, Columbia University, New York, NY 10032; and.
authors: Nilushi S
authors: NS
authors: De Silva
authors: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032;
authors: Kathryn
authors: K
authors: Silva
authors: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032;
authors: Michael M
authors: MM
authors: Anderson
authors: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032.
authors: Govind
authors: http://orcid.org/0000-0001-6250-048X
authors: G
authors: Bhagat
authors: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032; Department of Microbiology and Immunology, Columbia University, New York, NY 10032; and Department of Pathology and Cell Biology, Columbia University, New York, NY 10032 uk30@cumc.columbia.edu.
authors: Ulf
authors: U
authors: Klein
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D002469:Cell Separation; D005434:Flow Cytometry; D006706:Homeostasis / Q000276:immunology*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000276:immunology* / Q000378:metabolism; D052003:NF-kappa B p52 Subunit / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D051841:Transcription Factor RelB / Q000276:immunology / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; C497594:Relb protein, mouse; D051841:Transcription Factor RelB