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A Toll-like receptor recognizes bacterial DNA

An Erratum to this article was published on 01 February 2001

Abstract

DNA from bacteria has stimulatory effects on mammalian immune cells1,2,3, 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 response4,5,6,7. Accumulating evidence has revealed the therapeutic potential of CpG DNA as adjuvants for vaccination strategies for cancer, allergy and infectious diseases8,9,10. 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.

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Figure 1: Amino-acid sequences and tissue distribution of TLR9.
Figure 2: Targeted disruption of the mouse Tlr9 gene.
Figure 3: Impaired responses to CpG ODN in TLR9-/- cells.
Figure 4: Resistance to CpG ODN-induced shock in TLR9-/- mice.

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Acknowledgements

We thank G. B. Lipford for helpful discussions; T. Aoki for secretarial assistance; and N. Tsuji, N. Iwami and E. Nakatani for technical assistance. We also thank Hayashibara Biochemical Laboratories, Inc. for providing anti-IRAK antibody. This work was supported in part by grants from the Ministry of Education, Science, Sports and Culture of Japan, and Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists.

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Correspondence to Shizuo Akira.

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Hemmi, H., Takeuchi, O., Kawai, T. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745 (2000). https://doi.org/10.1038/35047123

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