IRF8 governs expression of genes involved in innate and adaptive immunity in human and mouse germinal center B cells

PLoS One. 2011;6(11):e27384. doi: 10.1371/journal.pone.0027384. Epub 2011 Nov 11.

Abstract

IRF8 (Interferon Regulatory Factor 8) is a transcription factor expressed throughout B cell differentiation except for mature plasma cells. Previous studies showed it is part of the transcriptional network governing B cell specification and commitment in the bone marrow, regulates the distribution of mature B cells into the splenic follicular and marginal zone compartments, and is expressed at highest levels in germinal center (GC) B cells. Here, we investigated the transcriptional programs and signaling pathways affected by IRF8 in human and mouse GC B cells as defined by ChIP-chip analyses and transcriptional profiling. We show that IRF8 binds a large number of genes by targeting two distinct motifs, half of which are also targeted by PU.1. Over 70% of the binding sites localized to proximal and distal promoter regions with ∼25% being intragenic. There was significant enrichment among targeted genes for those involved in innate and adaptive immunity with over 30% previously defined as interferon stimulated genes. We also showed that IRF8 target genes contributes to multiple aspects of the biology of mature B cells including critical components of the molecular crosstalk among GC B cells, T follicular helper cells, and follicular dendritic cells.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adaptive Immunity / genetics
  • Adaptive Immunity / immunology*
  • Animals
  • B-Lymphocytes / immunology*
  • Blotting, Western
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Flow Cytometry
  • Germinal Center / immunology*
  • Germinal Center / metabolism*
  • Humans
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology*
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism*
  • Mice
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Trans-Activators / genetics
  • Trans-Activators / metabolism

Substances

  • Interferon Regulatory Factors
  • Proto-Oncogene Proteins
  • Trans-Activators
  • interferon regulatory factor-8
  • proto-oncogene protein Spi-1