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.