A Toll-like receptor recognizes bacterial DNA
A Toll-like receptor recognizes bacterial DNA
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DOI：
10.1038/35047123
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发表时间：
2000-12-07
期刊：
影响因子：
64.8
通讯作者：
Akira, S
中科院分区：
文献类型：
--
作者：
Hemmi, H;Takeuchi, O;Akira, S
来自细菌的DNA对哺乳动物免疫细胞具有刺激作用（1-3），这取决于细菌DNA中未甲基化的CpG二核苷酸的存在。相比之下，哺乳动物DNA具有低频率的CpG二核苷酸，并且这些二核苷酸大多是甲基化的;因此，哺乳动物DNA不具有免疫刺激活性。CpG DNA诱导强烈的T辅助细胞-1样炎症反应（4-7）。越来越多的证据已经揭示了CpG DNA作为癌症、过敏和传染病疫苗接种策略的佐剂的治疗潜力（8-10）。尽管CpG DNA具有良好的临床应用前景，但其激活免疫细胞的分子机制仍不清楚。在这里，我们表明，细胞对CpG DNA的反应是由Toll样受体TLR 9介导的。TLR 9缺陷型（TLR 9（-/-））小鼠对CpG DNA没有任何反应，包括脾细胞增殖、巨噬细胞产生炎性细胞因子和树突状细胞成熟。TLR 9（-/-）小鼠对CPG DNA的致死作用表现出抗性，而血清促炎细胞因子水平没有任何升高。在TLR 9（-/-）小鼠体内CpG-DNA介导的1型辅助性T细胞应答也被消除。因此，脊椎动物的免疫系统似乎已经进化出一种特异性的Toll样受体，可以将细菌DNA与自身DNA区分开来。
DNA from bacteria has stimulatory effects on mammalian immune cells(1-3) which depend on the presence of unmethylated CpG dinucleotides in the bacterial DNA. In contrast, mammalian DNA has a low frequency of CpG dinucleotides, and these are mostly methylated; therefore, mammalian DNA does not have immune-stimulatory activity. CpG DNA induces a strong T-helper-1-like inflammatory response(4-7). Accumulating evidence has revealed the therapeutic potential of CpG DNA as adjuvants for vaccination strategies for cancer, allergy and infectious diseasess(8-10). Despite its promising clinical use, the molecular mechanism by which CpG DNA activates immune cells remains unclear. Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. TLR9-deficient (TLR9(-/-)) mice did not show any response to CpG DNA, including proliferation of splenocytes, inflammatory Cytokine production from macrophages and maturation of dendritic cells. TLR9(-/-) mice showed resistance to the lethal effect of CPG DNA without any elevation of serum pro-inflammatory cytokine levels. The in vivo CpG-DNA-mediated T-helper type-1 response was also abolished in TLR9(-/-) mice. Thus, vertebrate immune systems appear to have evolved a specific Toll-like receptor that distinguishes bacterial DNA from self-DNA.