PI3 Kinase and FOXO1 Transcription Factor Activity Differentially Control B Cells in the Germinal Center Light and Dark Zones

• Published in: Immunity (Cambridge, Mass.) Vol. 43; no. 6; pp. 1075 - 1086
• Main Authors: Sander, Sandrine, Chu, Van Trung, Yasuda, Tomoharu, Franklin, Andrew, Graf, Robin, Calado, Dinis Pedro, Li, Shuang, Imami, Koshi, Selbach, Matthias, Di Virgilio, Michela, Bullinger, Lars, Rajewsky, Klaus
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-12-2015; Elsevier Limited
• Subjects: Animals; B-Lymphocytes - cytology; B-Lymphocytes - immunology; Bone marrow; Cell Differentiation - immunology; Cell Separation; Chromatography, Liquid; Cytidine Deaminase - immunology; Experiments; Flow Cytometry; Fluorescent Antibody Technique; Forkhead Box Protein O1; Forkhead Transcription Factors - immunology; Gene expression; Gene Expression Regulation - immunology; Genomes; Germinal Center - cytology; Germinal Center - immunology; Immunoglobulin Class Switching - immunology; Kinases; Lymphocyte Activation - immunology; Mice; Mice, Mutant Strains; Phosphatidylinositol 3-Kinases - immunology; Polymerase Chain Reaction; Rodents; Scientific imaging; Somatic Hypermutation, Immunoglobulin - immunology; Tandem Mass Spectrometry; Transcription factors
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2015.10.021

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).
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•PI3K signaling and FOXO1 are antagonistic master regulators of the GC reaction•FOXO1 is essential for the proliferating GC compartment, the dark zone•Selection, but not generation, of somatic antibody mutants is controlled by FOXO1•FOXO1 controls isotype switching in GCs through switch region accessibility for AID
The germinal center (GC) reaction is of key importance for adaptive immunity as well as the origin of most human B cell lymphomas. Using conditional targeted mutagenesis, Sander, Rajewsky, and colleagues identify PI3K signaling and the transcription factor FOXO1 as essential antagonistic regulators of GC polarization, antibody diversification, and cellular selection.