The Journal of Experimental Medicine
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Published online 17 January 2006 doi:10.1084/jem.20051645
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 1, 227-238
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ARTICLE

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

Nobuyuki Onai, Aya Obata-Onai, Roxane Tussiwand, Antonio Lanzavecchia, and Markus G. Manz

Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland

CORRESPONDENCE Markus G. Manz: manz{at}irb.unisi.ch

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-7R{alpha}–Thy1.1–c-Kit+) and Flt3+ (Flt3+Lin–IL-7R{alpha}–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.

Abbreviations used: CLP, common lymphoid progenitor; CMP, common myeloid progenitor; Flt3 ligand, Flt3L; GM, granulocyte/macrophage; GMP, GM progenitor; HSC, hematopoietic stem cell; IPC, type I interferon-producing cell; MEP, megakaryocyte/erythrocyte progenitor; SCF, stem cell factor; TPO, thrombopoietin.

N. Onai and A. Obata-Onai contributed equally to this work.


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