title: PI3 Kinase and FOXO1 Transcription Factor Activity Differentially Control B Cells in the Germinal Center Light and Dark Zones.
abstract: Phosphatidylinositol 3' OH kinase (PI3K) signaling and FOXO transcription factors play opposing roles at several B cell developmental stages. We show here abundant nuclear FOXO1 expression in the proliferative compartment of the germinal center (GC), its dark zone (DZ), and PI3K activity, downregulating FOXO1, in the light zone (LZ), where cells are selected for further differentiation. In the LZ, however, FOXO1 was expressed in a fraction of cells destined for DZ reentry. Upon FOXO1 ablation or induction of PI3K activity, GCs lost their DZ, owing at least partly to downregulation of the chemokine receptor CXCR4. Although this prevented proper cyclic selection of cells in GCs, somatic hypermutation and proliferation were maintained. Class switch recombination was partly lost due to a failure of switch region targeting by activation-induced deaminase (AID).
authors.affiliation: Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Alliance, Berlin-Buch 13125, Germany. Electronic address: sandrine.sander@mdc-berlin.de.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Sander
authors.affiliation: Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Alliance, Berlin-Buch 13125, Germany.
authors.forename: Van Trung
authors.initials: VT
authors.lastname: Chu
authors.affiliation: Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Alliance, Berlin-Buch 13125, Germany.
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Yasuda
authors.affiliation: Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Alliance, Berlin-Buch 13125, Germany.
authors.forename: Andrew
authors.initials: A
authors.lastname: Franklin
authors.affiliation: Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Alliance, Berlin-Buch 13125, Germany.
authors.forename: Robin
authors.initials: R
authors.lastname: Graf
authors.affiliation: Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Alliance, Berlin-Buch 13125, Germany; Cancer Research UK, London Research Institute, London WC2A 3LY, UK; Peter Gorer Department of Immunobiology, Kings College London, London SE1 9RT, UK.
authors.forename: Dinis Pedro
authors.initials: DP
authors.lastname: Calado
authors.affiliation: Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Alliance, Berlin-Buch 13125, Germany.
authors.forename: Shuang
authors.initials: S
authors.lastname: Li
authors.affiliation: Proteome Dynamics, Max Delbrück Center for Molecular Medicine in the Helmholtz Alliance, Berlin-Buch 13125, Germany.
authors.forename: Koshi
authors.initials: K
authors.lastname: Imami
authors.affiliation: Proteome Dynamics, Max Delbrück Center for Molecular Medicine in the Helmholtz Alliance, Berlin-Buch 13125, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Selbach
authors.affiliation: DNA Repair and Maintenance of Genome Stability, Max Delbrück Center for Molecular Medicine in the Helmholtz Alliance, Berlin-Buch 13125, Germany.
authors.forename: Michela
authors.initials: M
authors.lastname: Di Virgilio
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm 89081, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.affiliation: Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Alliance, Berlin-Buch 13125, Germany. Electronic address: klaus.rajewsky@mdc-berlin.de.
authors.forename: Klaus
authors.initials: K
authors.lastname: Rajewsky
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D002853:Chromatography, Liquid; D003564:Cytidine Deaminase / Q000276:immunology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D018858:Germinal Center / Q000166:cytology / Q000276:immunology*; D017578:Immunoglobulin Class Switching / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology*; D016133:Polymerase Chain Reaction; D027041:Somatic Hypermutation, Immunoglobulin / Q000276:immunology; D053719:Tandem Mass Spectrometry; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase