title: A Temporal Switch in the Germinal Center Determines Differential Output of Memory B and Plasma Cells.
abstract: There is little insight into or agreement about the signals that control differentiation of memory B cells (MBCs) and long-lived plasma cells (LLPCs). By performing BrdU pulse-labeling studies, we found that MBC formation preceded the formation of LLPCs in an adoptive transfer immunization system, which allowed for a synchronized Ag-specific response with homogeneous Ag-receptor, yet at natural precursor frequencies. We confirmed these observations in wild-type (WT) mice and extended them with germinal center (GC) disruption experiments and variable region gene sequencing. We thus show that the GC response undergoes a temporal switch in its output as it matures, revealing that the reaction engenders both MBC subsets with different immune effector function and, ultimately, LLPCs at largely separate points in time. These data demonstrate the kinetics of the formation of the cells that provide stable humoral immunity and therefore have implications for autoimmunity, for vaccine development, and for understanding long-term pathogen resistance.
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Florian J
authors.initials: FJ
authors.lastname: Weisel
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Griselda V
authors.initials: GV
authors.lastname: Zuccarino-Catania
authors.affiliation: Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Chikina
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: mshlomch@pitt.edu.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Shlomchik
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D018858:Germinal Center / Q000166:cytology / Q000276:immunology*; D056724:Immunity, Humoral / Q000276:immunology; D007150:Immunohistochemistry; D007156:Immunologic Memory / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010950:Plasma Cells / Q000166:cytology* / Q000276:immunology; D013997:Time Factors