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

被引:125
作者
Onai, N [1 ]
Obata-Onai, A [1 ]
Tussiwand, R [1 ]
Lanzavecchia, A [1 ]
Manz, MG [1 ]
机构
[1] Inst Res Biomed, CH-6500 Bellinzona, Switzerland
关键词
D O I
10.1084/jem.20051645
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:227 / 238
页数:12
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