Flt3 in regulation of type I interferon-producing cell and dendritic cell development.
Flt3-ligand is a nonredundant cytokine in type I interferon-producing cell (IPC) and dendritic cell (DC) development. We demonstrated that IPC and DC differentiation potential is confined to Flt3(+)-hematopoietic progenitor cells, that Flt3-ligand drives development along both lymphoid and myeloid developmental pathways from Flt3(+)-progenitors to Flt3(+)-IPCs and -DCs, and that in vivo pharmacologic inhibition of Flt3-signaling leads to disruption of IPC and DC development in spite of consecutive Flt3-ligand upregulation in treated animals. We here summarize our recent findings that overexpression of human Flt3 in Flt3(-) and Flt3(+) hematopoietic progenitors rescues and enhances their IPC and DC differentiation potential, respectively. Based on these data, we propose an instructive, demand-regulated, cytokine-driven IPC and DC regeneration model, where high Flt3-ligand levels initiate a self-sustaining, Flt3-STAT3 and -PU.1-mediated IPC and DC differentiation program in Flt3(+)-hematopoietic progenitor cells.
Onai
Nobuyuki
N
Institute for Research in Biomedicine (IRB), Via Vincenzo Vela 6, CH-6500 Bellinzona, Switzerland.
Obata-Onai
Aya
A
Schmid
Michael A
MA
Manz
Markus G
MG
D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation; D000099232:Proto-Oncogene Protein Spi-1
D007370:Interferon Type I; D008024:Ligands; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C084881:flt3 ligand protein