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A Toll-like receptor recognizes bacterial DNA

Author

Listed:
  • Hiroaki Hemmi

    (Research Institute for Microbial Diseases, Osaka University
    Japan Science and Technology Corporation)

  • Osamu Takeuchi

    (Research Institute for Microbial Diseases, Osaka University
    Japan Science and Technology Corporation)

  • Taro Kawai

    (Research Institute for Microbial Diseases, Osaka University
    Japan Science and Technology Corporation)

  • Tsuneyasu Kaisho

    (Research Institute for Microbial Diseases, Osaka University
    Japan Science and Technology Corporation)

  • Shintaro Sato

    (Research Institute for Microbial Diseases, Osaka University
    Japan Science and Technology Corporation)

  • Hideki Sanjo

    (Research Institute for Microbial Diseases, Osaka University
    Japan Science and Technology Corporation)

  • Makoto Matsumoto

    (Research Institute for Microbial Diseases, Osaka University
    Japan Science and Technology Corporation)

  • Katsuaki Hoshino

    (Research Institute for Microbial Diseases, Osaka University
    Japan Science and Technology Corporation)

  • Hermann Wagner

    (Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich)

  • Kiyoshi Takeda

    (Research Institute for Microbial Diseases, Osaka University
    Japan Science and Technology Corporation)

  • Shizuo Akira

    (Research Institute for Microbial Diseases, Osaka University
    Japan Science and Technology Corporation)

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.

Suggested Citation

  • Hiroaki Hemmi & Osamu Takeuchi & Taro Kawai & Tsuneyasu Kaisho & Shintaro Sato & Hideki Sanjo & Makoto Matsumoto & Katsuaki Hoshino & Hermann Wagner & Kiyoshi Takeda & Shizuo Akira, 2000. "A Toll-like receptor recognizes bacterial DNA," Nature, Nature, vol. 408(6813), pages 740-745, December.
    • Handle: RePEc:nat:nature:v:408:y:2000:i:6813:d:10.1038_35047123
    DOI: 10.1038/35047123
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    Cited by:

    1. Eileen Rauch & Timm Amendt & Aleksandra Lopez Krol & Fabian B. Lang & Vincent Linse & Michelle Hohmann & Ann-Christin Keim & Susanne Kreutzer & Kevin Kawengian & Malte Buchholz & Philipp Duschner & Sa, 2024. "T-bet+ B cells are activated by and control endogenous retroviruses through TLR-dependent mechanisms," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Srujan Kumar Dondapati & Georg Pietruschka & Lena Thoring & Doreen A Wüstenhagen & Stefan Kubick, 2019. "Cell-free synthesis of human toll-like receptor 9 (TLR9): Optimization of synthesis conditions and functional analysis," PLOS ONE, Public Library of Science, vol. 14(4), pages 1-16, April.
    3. M. Clement & J. L. Forbester & M. Marsden & P. Sabberwal & M. S. Sommerville & D. Wellington & S. Dimonte & S. Clare & K. Harcourt & Z. Yin & L. Nobre & R. Antrobus & B. Jin & M. Chen & S. Makvandi-Ne, 2022. "IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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