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Cited by 156Immunotherapy and Immune ResponsesCytokine Signaling Pathways and InteractionsHematopoietic Stem Cell Transplantation

Activation of the Flt3 signal transduction cascade rescues and enhances type I interferon-producing and dendritic cell development

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Onai, Nobuyuki, Obata-Onai, Aya, Tussiwand, Roxane, Lanzavecchia, Antonio, Manz, Markus G.·2006·The Journal of Experimental Medicine
DOI 10.1084/jem.20051645PMC PMC2118073
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Abstract

Flt3 ligand (Flt3L) is a nonredundant cytokine in type I interferon–producing cell (IPC) and dendritic cell (DC) development, and IPC and DC differentiation potential is confined to Flt3+ hematopoietic progenitor cells. Here, we show that overexpression of human Flt3 in Flt3− (Flt3−Lin−IL-7Rα−Thy1.1−c-Kit+) and Flt3+ (Flt3+Lin−IL-7Rα−Thy1.1−c-Kit+) hematopoietic progenitors rescues and enhances their IPC and DC differentiation potential, respectively. In defined hematopoietic cell populations, such as Flt3− megakaryocyte/erythrocyte-restricted progenitors (MEPs), enforced Flt3 signaling induces transcription of IPC, DC, and granulocyte/macrophage (GM) development–affiliated genes, including STAT3, PU.1, and G-/M-/GM-CSFR, and activates differentiation capacities to these lineages. Moreover, ectopic expression of Flt3 downstream transcription factors STAT3 or PU.1 in Flt3− MEPs evokes Flt3 receptor expression and instructs differentiation into IPCs, DCs, and myelomonocytic cells, whereas GATA-1 expression and consecutive megakaryocyte/erythrocyte development is suppressed. Based on these data, we propose a demand-regulated, cytokine-driven DC and IPC regeneration model, in which high Flt3L levels initiate a self-sustaining, Flt3-STAT3– and Flt3-PU.1–mediated IPC and DC differentiation program in Flt3+ hematopoietic progenitor cells.

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Cited by

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Authors
Onai, N., Obata-Onai, A., Tussiwand, R., Lanzavecchia, A., & Manz, M. G.
Affiliations
Institute for Research in Biomedicine (CH)
ORCID
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2006-01-17
Volume
203
Issue
1
Pages
227-238
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20051645
PMC
PMC2118073
OpenAlex
W2101595031
Cited by
156
References
8
Citations by year
2026: 1 · 2025: 4 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 4 · 2019: 7 · 2018: 8 · 2017: 10 · 2016: 4 · 2015: 8 · 2014: 9 · 2013: 16 · 2012: 13
FWCI
4.43
Type
journal article
Language
en
Open access
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
Keywords
FLT3, Flt3 ligand, dendritic cell development, hematopoietic progenitor cells, megakaryocyte-erythrocyte progenitors, STAT3, PU.1, GATA-1, GM-CSF receptor, myelomonocytic differentiation, hematopoietic differentiation
MeSH terms
Proto-Oncogene Protein Spi-1, Animals, Cell Differentiation, Dendritic Cells, Hematopoietic Stem Cells, Humans, Interferon Type I, Mice, Inbred BALB C, Mice, Inbred C57BL, Proto-Oncogene Proteins, Signal Transduction, Trans-Activators, STAT3 Transcription Factor, Mice, fms-Like Tyrosine Kinase 3

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