Defective development of splenic and epidermal CD4+ dendritic cells in mice deficient for IFN regulatory factor-2
Defective development of splenic and epidermal CD4+ dendritic cells in mice deficient for IFN regulatory factor-2
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DOI：
10.1073/pnas.0400610101
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发表时间：
2004-03-16
影响因子：
11.1
通讯作者：
Taki, S
中科院分区：
文献类型：
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作者：
Ichikawa, E;Hida, S;Taki, S
树突状细胞在免疫应答的启动和调控中起着重要的作用。尽管根据其表面分子如CD4、CD8和CD11b的表达确定了几个DC亚群，但这些DC亚群发育和稳态的调控机制尚不清楚。在这里，我们发现缺乏IFN调节因子-2的小鼠（IRF-2（-/-）小鼠）在脾脏CD4(+)CD11b(+) dc中表现出明显的选择性缺陷，而不是在缺乏相关转录因子IRF-8的小鼠中缺失的CD8alpha(+)CD11b(-) dc。此外，IRF2（-/-）小鼠表皮朗格汉斯细胞的数量减少，至少部分原因是缺乏CD4(+)CD11b（+）亚群。对放射骨髓嵌合体以及体外逆转录病毒介导的基因转导的研究表明，IRF-2是骨髓相关dc的细胞自主发展所必需的。值得注意的是，在缺乏IRF-2和ifn - α / β受体的小鼠中，dc中的这些异常减少，表明IRF-2通过负向调节ifn - α / β信号起作用。相比之下，自然杀伤细胞在这些双突变小鼠中仍然表现出发育停滞，这表明IRF-2对CD4(+)DC发育的作用方式与自然杀伤细胞发育的作用方式不同。因此，我们目前的研究结果指出了IRF-2在调节淋巴造血中的一种以前未知的独特的细胞类型选择性多模式功能。
Dendritic cells (DCs) play important roles in the initiation and regulation of immune responses. Although several subsets of DCs were identified according to their expression of surface molecules such as CD4, CD8, and CD11b, the regulatory mechanism for the development and homeostasis of these DC subsets remains unclear. Here we show that mice lacking IFN regulatory factor-2 (IRF-2(-/-) mice) exhibited a marked and selective defect in splenic CD4(+)CD11b(+)DCs, instead of CD8alpha(+)CD11b(-)DCs that were reported to be missing in mice lacking the related transcription factor IRF-8. Furthermore, the numbers of epidermal Langerhans cells in IRF2(-/-) mice were reduced at least in part because of the lack of the CD4(+)CD11b(+) subset. Studies with radiation bone marrow chimeras as well as in vitro retrovirus-mediated gene transduction showed that IRF-2 was required cell-autonomously for the development of myeloid-related DCs. Notably, these abnormalities in DCs diminished in mice lacking both IRF-2 and the IFN-alpha/beta receptor, indicating that IRF-2 acted through negatively regulating IFN-alpha/beta signals. In contrast, natural killer cells still showed developmental arrest in these double mutant mice, indicating that the mode of action of IRF-2 for CD4(+)DC development is distinct from that for natural killer cell development. Our current findings thus pointed to a previously unknown unique cell-type-selective multimode function of IRF-2 in the regulation of lymphohematopoiesis.