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a Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland b Department of Immunology, University of Akita, School of Medicine, Akita 010-8543, Japan c Department of Hematology, Oncology, and Immunology, Eberhard-Karls-University Medical School, 42076 Tübingen, Germany
Key Words: Flt3 • hematopoiesis • dendritic cells
Address for correspondence: Markus G. Manz, M.D., Institute for Research in Biomedicine (IRB), Via Vincenzo Vela 6, CH-6500 Bellinzona, Switzerland. Voice: +41-91-820-0361; fax: +41-91-820-0312. manz{at}irb.unisi.ch
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.
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