title: Regulation of bifurcating B cell trajectories by mutual antagonism between transcription factors IRF4 and IRF8.
abstract: Upon recognition of antigen, B cells undertake a bifurcated response in which some cells rapidly differentiate into plasmablasts while others undergo affinity maturation in germinal centers (GCs). Here we identified a double-negative feedback loop between the transcription factors IRF4 and IRF8 that regulated the initial developmental bifurcation of activated B cells as well as the GC response. IRF8 dampened signaling via the B cell antigen receptor (BCR), facilitated antigen-specific interaction with helper T cells, and promoted antibody affinity maturation while antagonizing IRF4-driven differentiation of plasmablasts. Genomic analysis revealed concentration-dependent actions of IRF4 and IRF8 in regulating distinct gene-expression programs. Stochastic modeling suggested that the double-negative feedback was sufficient to initiate bifurcation of the B cell developmental trajectories.
authors.affiliation: Division of Immunobiology and the Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Heping
authors.initials: H
authors.lastname: Xu
authors.affiliation: Division of Immunobiology and the Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Virendra K
authors.initials: VK
authors.lastname: Chaudhri
authors.affiliation: Division of Immunobiology and the Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Division of Immunobiology and the Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Biliouris
authors.affiliation: Division of Immunobiology and the Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Krista
authors.initials: K
authors.lastname: Dienger-Stambaugh
authors.affiliation: Division of Immunobiology and the Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Yrina
authors.initials: Y
authors.lastname: Rochman
authors.affiliation: Division of Immunobiology and the Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Harinder
authors.initials: H
authors.lastname: Singh
mesh_terms: D000465:Algorithms; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D025461:Feedback, Physiological; D005434:Flow Cytometry; D018858:Germinal Center / Q000166:cytology / Q000276:immunology; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018448:Models, Immunological; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics / Q000276:immunology; D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D011947:Receptors, Antigen, B-Cell; D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4