The FOXO1 Transcription Factor Instructs the Germinal Center Dark Zone Program

Immunity. 2015 Dec 15;43(6):1064-74. doi: 10.1016/j.immuni.2015.10.015. Epub 2015 Nov 24.


The pathways regulating formation of the germinal center (GC) dark zone (DZ) and light zone (LZ) are unknown. In this study we show that FOXO1 transcription factor expression was restricted to the GC DZ and was required for DZ formation, since its absence in mice led to the loss of DZ gene programs and the formation of LZ-only GCs. FOXO1-negative GC B cells displayed normal somatic hypermutation but defective affinity maturation and class switch recombination. The function of FOXO1 in sustaining the DZ program involved the trans-activation of the chemokine receptor CXCR4, and cooperation with the BCL6 transcription factor in the trans-repression of genes involved in immune activation, DNA repair, and plasma cell differentiation. These results also have implications for the role of FOXO1 in lymphomagenesis because they suggest that constitutive FOXO1 activity might be required for the oncogenic activity of deregulated BCL6 expression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology*
  • Cell Differentiation / immunology*
  • Chromatin Immunoprecipitation
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / immunology*
  • Germinal Center / cytology
  • Germinal Center / immunology*
  • Humans
  • Immunoglobulin Class Switching / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Polymerase Chain Reaction
  • Somatic Hypermutation, Immunoglobulin / immunology


  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse

Associated data

  • GEO/GSE68349
  • GEO/GSE69216