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.

Transcription factor networks in dendritic cell development

“…In addition, different cytokines appear to have varying effects on the development of specific DC subsets. For instance, GM-CSF favors the development of cDCs while inhibiting the development of pDCs, through a mechanism dependent upon activation of STAT5 [70]. In contrast, culturing bone marrow cells in M-CSF in combination with Flt3L has the opposite effect, favoring pDC development [51].…”

Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

“…While STAT3 activation is not crucial for EPO-R activity (Menon et al, 2006), and its role in erythropoiesis is still not clear, it plays a prominent role in development and maturation 19 of DCs (Laouar et al, 2003;Tian et al, 2007). In that respect, STAT5 signaling is associated with inhibition of DC development (Esashi et al, 2008).…”

The network of cytokines, receptors and transcription factors governing the development of dendritic cell subsets

“…As discussed above, it has been suggested that Stat5 activation suppresses the differentiation of pDC (Esashi et al, 2008). Stat5 deficient mice show slight reductions in lymphoid organ DC (Vremec et al, 1997;Esashi et al, 2008), echoing the phenotype of GM-CSFR deficient mice.…”

“…The addition of GM-CSF to FL stimulated cultures blocked pDC development from lin − Flt3 + progenitors, via an Stat5 dependent mechanism (Esashi et al, 2008). This abrogation of pDC development was shown to be the result of suppression of Irf8, a crucial transcription factor in pDC development, by Stat5.…”

“…Alternatively, upon upregulation of Id2, and the retention of high levels of PU.1 expression, CDP can differentiate into pre-cDC. Exposure of CDP to GM-CSF, and the subsequent activation of Stat5 and suppression of Irf8, which actively suppresses differentiation of pDC and the equivalent of CD8 + DC (Esashi et al, 2008), lead to the production of DC similar to monocyte-derived DC. Irf8 has also been shown to have a role in the development of CD8 + and CD103 + cDC (Schiavoni et al, 2002;Aliberti et al, 2003a;Schiavoni et al, 2004;Edelson et al, 2010), both of which develop via pre-cDC.…”