Activation of the Flt3 signal transduction cascade rescues and enhances type I interferon-producing and dendritic cell development.
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-7Ralpha(-)Thy1.1(-)c-Kit+) and Flt3+ (Flt3(+)Lin(-)IL-7Ralpha(-)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.
Onai
Nobuyuki
N
Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland.
Obata-Onai
Aya
A
Tussiwand
Roxane
R
Lanzavecchia
Antonio
A
Manz
Markus G
MG
D000818:Animals; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology*; D006801:Humans; D007370:Interferon Type I; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000276:immunology / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000276:immunology / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
D007370:Interferon Type I; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D051941:fms-Like Tyrosine Kinase 3; D000099232:Proto-Oncogene Protein Spi-1; C497970:FLT3 protein, human