A Toll-like receptor recognizes bacterial DNA.
Hemmi, Hiroaki *+; Takeuchi, Osamu *+; Kawai, Taro *+; Kaisho, Tsuneyasu *+; Sato, Shintaro *+; Sanjo, Hideki *+; Matsumoto, Makoto *+; Hoshino, Katsuaki *+; Wagner, Hermann ++; Takeda, Kiyoshi *+; Akira, Shizuo *+
[Letter]
Nature.
408(6813):740-745, December 7, 2000.
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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 immuno-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 diseases 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.
(C) 2000 Nature Publishing Group