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Immunity. 2015 Dec 15;43(6):1075-86. doi: 10.1016/j.immuni.2015.10.021. Epub 2015 Nov 24.

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

Author information

1
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.
2
Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Alliance, Berlin-Buch 13125, Germany.
3
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.
4
Proteome Dynamics, Max Delbrück Center for Molecular Medicine in the Helmholtz Alliance, Berlin-Buch 13125, Germany.
5
DNA Repair and Maintenance of Genome Stability, Max Delbrück Center for Molecular Medicine in the Helmholtz Alliance, Berlin-Buch 13125, Germany.
6
Department of Internal Medicine III, University Hospital Ulm, Ulm 89081, Germany.
7
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.

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).

PMID:
26620760
DOI:
10.1016/j.immuni.2015.10.021
[Indexed for MEDLINE]
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