The Signal Transducer STAT5 Inhibits Plasmacytoid Dendritic Cell Development by Suppressing Transcription Factor IRF8

Immunity. 2008 Apr;28(4):509-20. doi: 10.1016/j.immuni.2008.02.013. Epub 2008 Mar 13.

Abstract

The development of distinct dendritic cell (DC) subsets is regulated by cytokines. The ligand for the FMS-like tyrosine kinase 3 receptor (Flt3L) is necessary for plasmacytoid DC (pDC) and conventional DC (cDC) maturation. The cytokine GM-CSF inhibits Flt3L-driven pDC production while promoting cDC growth. We show that GM-CSF selectively utilized its signal transducer STAT5 to block Flt3L-dependent pDC development from the lineage-negative, Flt3+ (lin- Flt3+) bone-marrow subset. The signaling molecule STAT3, by contrast, was necessary for expansion of DC progenitors but not pDC maturation. In vivo, STAT5 suppressed pDC formation during repopulation of the DC compartment after bone-marrow ablation. GM-CSF-dependent STAT5 signaling rapidly extinguished pDC-related gene expression in lin- Flt3+ progenitors. Inspection of the Irf8 promoter revealed that STAT5 was recruited during GM-CSF-mediated suppression, indicating that STAT5 directly inhibited transcription of this critical pDC gene. Our results therefore show that GM-CSF controls the production of pDCs by employing STAT5 to suppress IRF8 and the pDC transcriptional network in lin- Flt3+ progenitors.

Publication types

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

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / immunology
  • Bone Marrow Cells / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Cell Lineage / genetics
  • Cell Lineage / immunology
  • Cells, Cultured
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism*
  • Granulocyte-Macrophage Colony-Stimulating Factor / physiology
  • Growth Inhibitors / physiology*
  • Interferon Regulatory Factors / antagonists & inhibitors*
  • Interferon Regulatory Factors / biosynthesis
  • Interferon Regulatory Factors / physiology
  • Mice
  • Mice, Knockout
  • Multipotent Stem Cells / cytology
  • Multipotent Stem Cells / immunology
  • Multipotent Stem Cells / metabolism
  • STAT5 Transcription Factor / deficiency
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / physiology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • fms-Like Tyrosine Kinase 3 / biosynthesis

Substances

  • Growth Inhibitors
  • Interferon Regulatory Factors
  • STAT5 Transcription Factor
  • interferon regulatory factor-8
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Flt3 protein, mouse
  • fms-Like Tyrosine Kinase 3