title: Transcription factors of the alternative NF-κB pathway are required for germinal center B-cell development.
abstract: The NF-κB signaling cascade relays external signals essential for B-cell growth and survival. This cascade is frequently hijacked by cancers that arise from the malignant transformation of germinal center (GC) B cells, underscoring the importance of deciphering the function of NF-κB in these cells. The NF-κB signaling cascade is comprised of two branches, the canonical and alternative NF-κB pathways, mediated by distinct transcription factors. The expression and function of the transcription factors of the alternative pathway, RELB and NF-κB2, in late B-cell development is incompletely understood. Using conditional deletion of relb and nfkb2 in GC B cells, we here report that ablation of both RELB and NF-κB2, but not of the single transcription factors, resulted in the collapse of established GCs. RELB/NF-κB2 deficiency in GC B cells was associated with impaired cell-cycle entry and reduced expression of the cell-surface receptor inducible T-cell costimulator ligand that promotes optimal interactions between B and T cells. Analysis of human tonsillar tissue revealed that plasma cells and their precursors in the GC expressed high levels of NF-κB2 relative to surrounding lymphocytes. Accordingly, deletion of nfkb2 in murine GC B cells resulted in a dramatic reduction of antigen-specific antibody-secreting cells, whereas deletion of relb had no effect. These results demonstrate that the transcription factors of the alternative NF-κB pathway control distinct stages of late B-cell development, which may have implications for B-cell malignancies that aberrantly activate this pathway.
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032; Department of Microbiology and Immunology, Columbia University, New York, NY 10032;
authors.forename: Nilushi S
authors.initials: NS
authors.lastname: De Silva
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032;
authors.forename: Michael M
authors.initials: MM
authors.lastname: Anderson
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032;
authors.forename: Amanda
authors.initials: A
authors.lastname: Carette
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032;
authors.forename: Kathryn
authors.initials: K
authors.lastname: Silva
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032;
authors.forename: Nicole
authors.initials: N
authors.lastname: Heise
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032.
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032; Department of Microbiology and Immunology, Columbia University, New York, NY 10032; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032 uk30@cumc.columbia.edu.
authors.forename: Ulf
authors.initials: U
authors.lastname: Klein
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D019013:CD40 Antigens / Q000502:physiology; D002478:Cells, Cultured; D018858:Germinal Center / Q000502:physiology*; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D051841:Transcription Factor RelB / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D019013:CD40 Antigens; D016328:NF-kappa B; C497594:Relb protein, mouse; D014157:Transcription Factors; D051841:Transcription Factor RelB
keywords: NF-κB transcription factors; germinal center B cell; plasma cell