共 54 条
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.
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页码:227 / 238
页数:12
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