title: The AP-1 transcription factor Fra1 inhibits follicular B cell differentiation into plasma cells.
abstract: The cornerstone of humoral immunity is the differentiation of B cells into antibody-secreting plasma cells. This process is tightly controlled by a regulatory gene network centered on the transcriptional repressor B lymphocyte-induced maturation protein 1 (Blimp1). Proliferation of activated B cells is required to foster Blimp1 expression but needs to be terminated to avoid overshooting immune reactions. Activator protein 1 (AP-1) transcription factors become quickly up-regulated upon B cell activation. We demonstrate that Fra1, a Fos member of AP-1, enhances activation-induced cell death upon induction in activated B cells. Moreover, mice with B cell-specific deletion of Fra1 show enhanced plasma cell differentiation and exacerbated antibody responses. In contrast, transgenic overexpression of Fra1 blocks plasma cell differentiation and immunoglobulin production, which cannot be rescued by Bcl2. On the molecular level, Fra1 represses Blimp1 expression and interferes with binding of the activating AP-1 member c-Fos to the Blimp1 promoter. Conversely, overexpression of c-Fos in Fra1 transgenic B cells releases Blimp1 repression. As Fra1 lacks transcriptional transactivation domains, we propose that Fra1 inhibits Blimp1 expression and negatively controls plasma cell differentiation through binding to the Blimp1 promoter. In summary, we demonstrate that Fra1 negatively controls plasma cell differentiation by repressing Blimp1 expression.
authors.affiliation: Division of Molecular Immunology, Nikolaus Fiebiger Center, Department of Internal Medicine III, Department of Radiation Oncology, Division of Ophthalmology, Department Kopfklinik, University of Erlangen-Nuremberg, D91054 Erlangen, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Grötsch
authors.affiliation: Division of Molecular Immunology, Nikolaus Fiebiger Center, Department of Internal Medicine III, Department of Radiation Oncology, Division of Ophthalmology, Department Kopfklinik, University of Erlangen-Nuremberg, D91054 Erlangen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brachs
authors.affiliation: Division of Molecular Immunology, Nikolaus Fiebiger Center, Department of Internal Medicine III, Department of Radiation Oncology, Division of Ophthalmology, Department Kopfklinik, University of Erlangen-Nuremberg, D91054 Erlangen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Lang
authors.affiliation: Division of Molecular Immunology, Nikolaus Fiebiger Center, Department of Internal Medicine III, Department of Radiation Oncology, Division of Ophthalmology, Department Kopfklinik, University of Erlangen-Nuremberg, D91054 Erlangen, Germany Institute for Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, D20246 Hamburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Luther
authors.affiliation: Division of Molecular Immunology, Nikolaus Fiebiger Center, Department of Internal Medicine III, Department of Radiation Oncology, Division of Ophthalmology, Department Kopfklinik, University of Erlangen-Nuremberg, D91054 Erlangen, Germany Division of Molecular Immunology, Nikolaus Fiebiger Center, Department of Internal Medicine III, Department of Radiation Oncology, Division of Ophthalmology, Department Kopfklinik, University of Erlangen-Nuremberg, D91054 Erlangen, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Derer
authors.affiliation: Division of Molecular Immunology, Nikolaus Fiebiger Center, Department of Internal Medicine III, Department of Radiation Oncology, Division of Ophthalmology, Department Kopfklinik, University of Erlangen-Nuremberg, D91054 Erlangen, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Schlötzer-Schrehardt
authors.affiliation: Division of Molecular Immunology, Nikolaus Fiebiger Center, Department of Internal Medicine III, Department of Radiation Oncology, Division of Ophthalmology, Department Kopfklinik, University of Erlangen-Nuremberg, D91054 Erlangen, Germany.
authors.forename: Aline
authors.initials: A
authors.lastname: Bozec
authors.affiliation: German Rheumatism Research Center (DRFZ), a Leibniz Institute, D10117 Berlin, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Fillatreau
authors.affiliation: Institute for Virology und Immunobiology, University of Würzburg, D97078 Würzburg, Germany.
authors.forename: Ingolf
authors.initials: I
authors.lastname: Berberich
authors.affiliation: BIOSS Centre for Biological Signalling Studies, Department of Molecular Immunology, Biology III, Faculty for Biology, and Max Planck Institute of Immunobiology and Epigenetics, University of Freiburg, D79108 Freiburg, Germany.
authors.forename: Elias
authors.initials: E
authors.lastname: Hobeika
authors.affiliation: BIOSS Centre for Biological Signalling Studies, Department of Molecular Immunology, Biology III, Faculty for Biology, and Max Planck Institute of Immunobiology and Epigenetics, University of Freiburg, D79108 Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Reth
authors.affiliation: Spanish National Cancer Center, Genes, Development and Disease Group, E28029 Madrid, Spain.
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
authors.affiliation: Division of Molecular Immunology, Nikolaus Fiebiger Center, Department of Internal Medicine III, Department of Radiation Oncology, Division of Ophthalmology, Department Kopfklinik, University of Erlangen-Nuremberg, D91054 Erlangen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.affiliation: Division of Molecular Immunology, Nikolaus Fiebiger Center, Department of Internal Medicine III, Department of Radiation Oncology, Division of Ophthalmology, Department Kopfklinik, University of Erlangen-Nuremberg, D91054 Erlangen, Germany j.david@uke.de dmielenz@molmed.uni-erlangen.de.
authors.forename: Dirk
authors.initials: D
authors.lastname: Mielenz
authors.affiliation: Division of Molecular Immunology, Nikolaus Fiebiger Center, Department of Internal Medicine III, Department of Radiation Oncology, Division of Ophthalmology, Department Kopfklinik, University of Erlangen-Nuremberg, D91054 Erlangen, Germany Institute for Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, D20246 Hamburg, Germany j.david@uke.de dmielenz@molmed.uni-erlangen.de.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: David
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology; D005786:Gene Expression Regulation; D056724:Immunity, Humoral; D056747:Immunomodulation; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D010950:Plasma Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099169:Fos-Related Antigen 1
chemical_list: D000074462:Positive Regulatory Domain I-Binding Factor 1; D016760:Proto-Oncogene Proteins c-fos; D014157:Transcription Factors; D000099169:Fos-Related Antigen 1; C513258:Prdm1 protein, mouse