A Toll-like receptor recognizes bacterial DNA

Hiroaki Hemmi, Osamu Takeuchi, Taro Kawai, Tsuneyasu Kaisho, Shintaro Sato, Hideki Sanjo, Makoto Matsumoto, Katsuaki Hoshino, Hermann Wagner, Kiyoshi Takeda and Shizuo Akira ()
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Hiroaki Hemmi: Research Institute for Microbial Diseases, Osaka University
Osamu Takeuchi: Research Institute for Microbial Diseases, Osaka University
Taro Kawai: Research Institute for Microbial Diseases, Osaka University
Tsuneyasu Kaisho: Research Institute for Microbial Diseases, Osaka University
Shintaro Sato: Research Institute for Microbial Diseases, Osaka University
Hideki Sanjo: Research Institute for Microbial Diseases, Osaka University
Makoto Matsumoto: Research Institute for Microbial Diseases, Osaka University
Katsuaki Hoshino: Research Institute for Microbial Diseases, Osaka University
Hermann Wagner: Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich
Kiyoshi Takeda: Research Institute for Microbial Diseases, Osaka University
Shizuo Akira: Research Institute for Microbial Diseases, Osaka University

Nature, 2000, vol. 408, issue 6813, 740-745

Abstract: 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.

Date: 2000
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DOI: 10.1038/35047123

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