The signal transducer STAT5 inhibits plasmacytoid dendritic cell development by suppressing transcription factor IRF8
Open accessAbstract
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.
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Flt3L activates STAT3 to stimulate dendritic cell progenitor proliferation.
“Fms-related tyrosine kinase 3 ligand, the major DC growth factor, activates STAT3 to stimulate DC progenitor proliferation”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Esashi et al., 2008
Leptin activates the JAK2/STAT3 signaling pathway in human B cells to induce IL-6 and TNF-α.
“Leptin activates the JAK2/STAT3 signaling pathway in human B cells to induce IL-6 and TNF-α”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Esashi et al., 2008
The signaling-results passage (Immunity section; page not specified) reports STAT3 activation by Flt3L and GM-CSF in dendritic-cell progenitors, not by leptin in human B cells. Searches for leptin, JAK2/STAT3 in human B cells, and IL-6 and TNF-α induction found no passage addressing the claim. (LLM, conf=0.77)
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Merad, M., Sathe, P., Helft, J., Miller, J., & Mortha, A. (2013) · Annual Review of Immunology · doi:10.1146/annurev-immunol-020711-074950 · Cited by 2,309 · see citing works
Mechanisms and consequences of Jak–STAT signaling in the immune system
Villarino, A. V., Kanno, Y., & O'Shea, J. J. (2017) · Nature Immunology · doi:10.1038/ni.3691 · Cited by 1,221 · see citing works
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“…transition of pre-pro-B cell progenitors to subsequent precursor populations and their survival (Chou et al., 2006) through Fms-related tyrosine kinase 3 ligand in Flt3-positive hematopoietic precursor cells, including common lymphocyte progenitor cells (McKenna et al., 2000; Esashi et al., 2008).”
BackgroundInfluentialSTAT3 controls myeloid progenitor growth during emergency granulopoiesis
Zhang, H., Nguyen-Jackson, H., Panopoulos, A. D., Li, H. S., Murray, P. J., & Watowich, S. S. (2010) · Blood · doi:10.1182/blood-2009-12-259630 · Cited by 232 · see citing works
Self-citationInoue, K., Qin, Y., Xia, Y., Han, J., Yuan, R., Sun, J., Xu, R., Jiang, J. X., Greenblatt, M. B., & Zhao, B. (2023) · eLife · doi:10.7554/elife.82118 · Cited by 65 · see citing works
- Authors
- Esashi, E., Wang, Y.-H., Perng, O., Qin, X.-F., Liu, Y.-J., & Watowich, S. S.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Liu, Yong-Jun
- Watowich, Stephanie S.
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2008-04
- Volume
- 28
- Issue
- 4
- Pages
- 509-520
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC2864148
- OpenAlex
- W1981253936
- Cited by
- 202
- References
- 1
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 5 · 2023: 5 · 2022: 10 · 2021: 9 · 2020: 10 · 2019: 11 · 2018: 9 · 2017: 10 · 2016: 14 · 2015: 9 · 2014: 21 · 2013: 16 · 2012: 22
- FWCI
- 7.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Gillson Longenbaugh Foundation
- National Institutes of Health (STAT3)
- National Institute of Allergy and Infectious Diseases (R21AI073587, R01AI059718)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- STAT5, plasmacytoid dendritic cells, IRF8, GM-CSF, Flt3L, dendritic cell development, STAT3, transcriptional repression, bone marrow progenitor cells, cytokine signaling, dendritic cell lineage
- MeSH terms
- Interferon Regulatory Factor-8, Animals, Bone Marrow Cells, Cell Differentiation, Cells, Cultured, Dendritic Cells, Growth Inhibitors, Signal Transduction, Granulocyte-Macrophage Colony-Stimulating Factor, Mice, Knockout, Cell Lineage, Multipotent Stem Cells, STAT5 Transcription Factor, Interferon Regulatory Factors, Mice, fms-Like Tyrosine Kinase 3
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