title: The signal transducer STAT5 inhibits plasmacytoid dendritic cell development by suppressing transcription factor IRF8.
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.
authors.affiliation: Department of Immunology and Center for Cancer Immunology Research, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Eiji
authors.initials: E
authors.lastname: Esashi
authors.forename: Yui-Hsi
authors.initials: YH
authors.lastname: Wang
authors.forename: Olivia
authors.initials: O
authors.lastname: Perng
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Qin
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Liu
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Watowich
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D006131:Growth Inhibitors / Q000502:physiology*; D050835:Interferon Regulatory Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D039902:Multipotent Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051941:fms-Like Tyrosine Kinase 3 / Q000096:biosynthesis; D000099185:Interferon Regulatory Factor-8
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006131:Growth Inhibitors; D050835:Interferon Regulatory Factors; D050799:STAT5 Transcription Factor; D051941:fms-Like Tyrosine Kinase 3; D000099185:Interferon Regulatory Factor-8; C497971:Flt3 protein, mouse