title: Germinal center B cell maintenance and differentiation are controlled by distinct NF-κB transcription factor subunits.
abstract: Germinal centers (GCs) are the sites where memory B cells and plasma cells producing high-affinity antibodies are generated during T cell-dependent immune responses. The molecular control of GC B cell maintenance and differentiation remains incompletely understood. Activation of the NF-κB signaling pathway has been implicated; however, the distinct roles of the individual NF-κB transcription factor subunits are unknown. We report that GC B cell-specific deletion of the NF-κB subunits c-REL or RELA, which are both activated by the canonical NF-κB pathway, abolished the generation of high-affinity B cells via different mechanisms acting at distinct stages during the GC reaction. c-REL deficiency led to the collapse of established GCs immediately after the formation of dark and light zones at day 7 of the GC reaction and was associated with the failure to activate a metabolic program that promotes cell growth. Conversely, RELA was dispensable for GC maintenance but essential for the development of GC-derived plasma cells due to impaired up-regulation of BLIMP1. These results indicate that activation of the canonical NF-κB pathway in GC B cells controls GC maintenance and differentiation through distinct transcription factor subunits. Our findings have implications for the role of NF-κB in GC lymphomagenesis.
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Department of Pathology and Cell Biology, and Department of Microbiology and Immunology, Columbia University, New York, NY 10032.
authors.forename: Nicole
authors.initials: N
authors.lastname: Heise
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Department of Pathology and Cell Biology, and 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, Department of Pathology and Cell Biology, and Department of Microbiology and Immunology, Columbia University, New York, NY 10032.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Silva
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Department of Pathology and Cell Biology, and Department of Microbiology and Immunology, Columbia University, New York, NY 10032.
authors.forename: Amanda
authors.initials: A
authors.lastname: Carette
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Department of Pathology and Cell Biology, and Department of Microbiology and Immunology, Columbia University, New York, NY 10032.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Simonetti
authors.affiliation: Institute of Genetics, University of Cologne, 50674 Cologne, Germany.
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Department of Pathology and Cell Biology, and Department of Microbiology and Immunology, Columbia University, New York, NY 10032 Herbert Irving Comprehensive Cancer Center, Department of Pathology and Cell Biology, and Department of Microbiology and Immunology, Columbia University, New York, NY 10032 Herbert Irving Comprehensive Cancer Center, Department of Pathology and Cell Biology, and Department of Microbiology and Immunology, Columbia University, New York, NY 10032 uk30@columbia.edu.
authors.forename: Ulf
authors.initials: U
authors.lastname: Klein
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005452:Fluoresceins; D017353:Gene Deletion; D018858:Germinal Center / Q000276:immunology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000276:immunology*; D013388:Succinimides; D051996:Transcription Factor RelA / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D005452:Fluoresceins; D016328:NF-kappa B; C513258:Prdm1 protein, mouse; D020569:Proto-Oncogene Proteins c-rel; D013388:Succinimides; D051996:Transcription Factor RelA; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1