Cited by 6,491Immune Response and InflammationImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

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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·2000·Nature

DOI 10.1038/35047123

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Abstract

DNA from bacteria has stimulatory effects on mammalian immune cells, 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. Accumulating evidence has revealed the therapeutic potential of CpG DNA as adjuvants for vaccination strategies for cancer, allergy and infectious diseases. 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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BackgroundResult
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Method
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BackgroundInfluentialSelf-citation
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BackgroundMethod
Apoptosis Induced by the Toll-Like Receptor Adaptor TRIF Is Dependent on Its Receptor Interacting Protein Homotypic Interaction Motif
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“The human genome encodes at least 10 TLRs (4–9), and the pathogen-associated molecules recognized by some TLRs have been identified such as peptidoglycan (TLR2) (10–12), dsRNA (TLR3) (13), LPS (TLR4) (14–16), flagellin (TLR5) (17), ssRNA (TLR7/8) (18–20), and unmethylated CpG DNA (TLR9) (21).”
Background
Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease
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Self-citation
Dendritic-cell function in Toll-like receptor- and MyD88-knockout mice
Kaisho, T., & Akira, S. (2001) · Trends in Immunology · doi:10.1016/s1471-4906(00)01811-1 · Cited by 369
Self-citation
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Method
Plasmacytoid dendritic cells sense skin injury and promote wound healing through type I interferons
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“…their unique intracellular expression of toll-like receptor (TLR) 7 and TLR9 (Kadowaki et al., 2001), which recognize single-stranded (ss) viral RNA and DNA transported into endosomal compartments by the virus infecting the cell (Hemmi et al., 2000, 2002; Diebold et al., 2004; Heil et al., 2004).”
Background
Intracellular DNA recognition
Hornung, V., & Latz, E. (2010) · Nature reviews. Immunology · doi:10.1038/nri2690 · Cited by 366
“The finding that TLR9 -deficient mice did not respond to CpG-rich DNA provided a molecular basis for most of the immune-stimulatory effects that were observed when microbial DNA was added to the extracellular space of cell”
Background
The E3 Ubiquitin Ligase AMFR and INSIG1 Bridge the Activation of TBK1 Kinase by Modifying the Adaptor STING
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Self-citation
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“TLR9 recognizes unmethlyated CpG DNA motifs of bacteria and viruses, and TLR9 activates high levels of type I IFN production, particularly IFNα, in pDCs and bone-marrow derived DCs (BMDCs)”
Background
Activation of the mammalian immune system by siRNAs
Marques, J. T., & Williams, B. R. G. (2005) · Nature Biotechnology · doi:10.1038/nbt1161 · Cited by 362
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“Tschopp and colleagues [63] demonstrated that the transfection of bacterial, viral, mammalian, or synthetic DNA additionally triggers the cleavage of caspase-1 and processing of IL-1b in an ASC-dependent manner, yet independent of TLR9, NLRC4, and NLRP3.”
Background
Initial responses to endotoxins and Gram-negative bacteria
Heumann, D., & Roger, T. (2002) · Clinica Chimica Acta · doi:10.1016/s0009-8981(02)00180-8 · Cited by 359
Neutrophil Gelatinase-Associated Lipocalin Is Up-Regulated in Human Epithelial Cells by IL-1β, but Not by TNF-α
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“For TLR2 and TLR4, use of the IL-1 pathway has been demonstrated (25, 47), and for TLR5 and TLR9, ligation of the receptor has been shown to cause an activation of NF- B (48, 49).”
Method
Various members of the Toll‐like receptor family contribute to the innate immune response of human epidermal keratinocytes
Köllisch, G. V., Kalali, B. N., Voelcker, V., Wallich, R., Behrendt, H., Ring, J., Bauer, S., Jakob, T., Mempel, M., & Ollert, M. W. (2005) · Immunology · doi:10.1111/j.1365-2567.2005.02122.x · Cited by 355
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“Moreover, Enterobacteriaceae present unmethylated immunostimulatory motifs that can induce an immune response through an interaction with TLR-9 [88].”
Background
Activation and regulation of Toll-like receptors 2 and 1 in human leprosy
Krutzik, S. R., Ochoa, M. T., Sieling, P. A., Uematsu, S., Ng, Y. W., Legaspi, A. J., Liu, P. T., Cole, S. T., Godowski, P. J., Maeda, Y., et al. (2003) · Nature Medicine · doi:10.1038/nm864 · Cited by 354
Self-citation
Does Toll-like receptor 3 play a biological role in virus infections?
Edelmann, K. H., Richardson-Burns, S. M., Alexopoulou, L., Tyler, K. L., Flavell, R. A., & Oldstone, M. B. A. (2004) · Virology · doi:10.1016/j.virol.2004.01.033 · Cited by 354
“, 2000), loss of TLR9 resulted in ablation of the immunostimulatory properties of bacterial DNA (Hemmi et al., 2000), and loss of TL4 resulted in increased susceptibility to respiratory syncytial virus (Kurt-Jones et al.”
Influential
MITOCHONDRIAL DNA IS RELEASED BY SHOCK AND ACTIVATES NEUTROPHILS VIA P38 MAP KINASE
Zhang, Q., Itagaki, K., & Hauser, C. J. (2010) · Shock · doi:10.1097/shk.0b013e3181cd8c08 · Cited by 361
“These data strongly suggest that mtDNA activates PMNs in part via TLR9.”
BackgroundInfluential
TLR4 Mediates Vaccine-Induced Protective Cellular Immunity to Bordetella pertussis : Role of IL-17-Producing T Cells
Higgins, S. C., Jarnicki, A., Lavelle, E. C., & Mills, K. H. G. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.11.7980 · Cited by 364
“However, innate immune responses also direct adaptive immunity, in part through the production of cytokines, such as IL-12, which promote Th1 cell differentiation (31, 32).”
Background
IκB kinase-α is critical for interferon-α production induced by Toll-like receptors 7 and 9
Hoshino, K., Sugiyama, T., Matsumoto, M., Tanaka, T., Saito, M., Hemmi, H., Ohara, O., Akira, S., & Kaisho, T. (2006) · Nature · doi:10.1038/nature04641 · Cited by 352
Self-citation
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“TLR9 is an intracellular molecule that functions as a sensor of DNA, and it was originally reported that TLR9 KO mice failed to respond to bacterial DNA, which is rich in unmethylated CpG.(28) Subsequently, TLR9 was shown to recognize endogenous DNA from mammalian cells.”
A comprehensive map of the toll‐like receptor signaling network
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“…Gram-negative bacteria in which LPS is a part of the outer membrane (Poltorak et al, 1998), TLR9 responds to DNA-containing unmethylated CpG motifs (Hemmi et al, 2000), TLR3 is activated by double-stranded RNA (Alexopoulou et al, 2001), and bacteria flagellin activates TLR5 (Hayashi et al, 2001).”
Background
Activation with CpG-A and CpG-B Oligonucleotides Reveals Two Distinct Regulatory Pathways of Type I IFN Synthesis in Human Plasmacytoid Dendritic Cells
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“These effects result from the high content of unmethylated ‘CpG motifs’ (3), which thereby enable TLR9 to effectively distinguish foreign prokaryotic DNAs from self-DNA (34).”
Background
BACTERIAL INTERACTIONS WITH CELLS OF THE INTESTINAL MUCOSA: TOLL-LIKE RECEPTORS AND NOD2
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Pathogen-specific regulatory T cells provoke a shift in the Th1/Th2 paradigm in immunity to infectious diseases
McGuirk, P., & Mills, K. H. G. (2002) · Trends in Immunology · doi:10.1016/s1471-4906(02)02288-3 · Cited by 349
Plasmacytoid Dendritic Cells Control TLR7 Sensitivity of Naive B Cells via Type I IFN
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Direct Binding of Toll-Like Receptor 2 to Zymosan, and Zymosan-Induced NF-κB Activation and TNF-α Secretion Are Down-Regulated by Lung Collectin Surfactant Protein A
Sato, M., Sano, H. I., Iwaki, D., Kudo, K., Konishi, M., Takahashi, H., Takahashi, T., Imaizumi, H., Asai, Y., & Kuroki, Y. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.1.417 · Cited by 348
MyD88-Dependent and MyD88-Independent Pathways in Synergy, Priming, and Tolerance between TLR Agonists
Bagchi, A., Herrup, E. A., Warren, H. S., Trigilio, J., Shin, H., Valentine, C., & Hellman, J. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.2.1164 · Cited by 338
Regulation of the type I IFN induction: a current view
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OAS proteins and cGAS: unifying concepts in sensing and responding to cytosolic nucleic acids
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“In 2000, TLR9 was identified as the first bona fide DNAsensing PRR 21 .”
Background
Molecular Chaperone Hsp90 Associates with Resistance Protein N and Its Signaling Proteins SGT1 and Rar1 to Modulate an Innate Immune Response in Plants
Liu, Y., Burch‐Smith, T. M., Schiff, M., Feng, S., & Dinesh‐Kumar, S. P. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m310029200 · Cited by 350
DNA damage sensor MRE11 recognizes cytosolic double-stranded DNA and induces type I interferon by regulating STING trafficking
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“Biochem Biophys Res Commun 265(3):716–721.”
Self-citation
Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody
Vicari, A. P., Chiodoni, C., Vaure, C., Aït-Yahia, S., Dercamp, C., Matsos, F., Reynard, O., Taverne, C., Merle, P., Colombo, M. P., et al. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20020732 · Cited by 343
“We tested different combinations of substances with the aim of relieving tumor-mediated inhibition and simultaneously mediating DC activation, including combinations of the TLR-9 ligand CpG 1668 (21) and an anti–IL-10R blocking antibody (15).”
Method
IFI16 senses DNA forms of the lentiviral replication cycle and controls HIV-1 replication
Jakobsen, M. R., Bak, R. O., Andersen, A., Berg, R. K., Jensen, S. B., Jin, T., Laustsen, A., Hansen, K., Østergaard, L., Fitzgerald, K. A., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1311669110 · Cited by 344
“Toll-like receptors (TLRs) detect viral nucleic acids in endosomes, with TLR3, -7/8, and -9 detecting dsRNA, ssRNA, and unmethylated DNA, respectively (5, 15, 16).”
Background
TIR domain-containing adaptors define the specificity of TLR signaling
Yamamoto, M., Takeda, K., & Akira, S. (2003) · Molecular Immunology · doi:10.1016/j.molimm.2003.10.006 · Cited by 344
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Authors: Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., Sato, S., Sanjo, H., Matsumoto, M., Hoshino, K., Wagner, H., Takeda, K., & Akira, S.
Affiliations: Research Institute for Microbial Diseases, The University of Osaka (JP)
Japan Science and Technology Agency (JP)
Technical University of Munich (DE)
Corresponding author: Akira, Shizuo
ORCID: Hemmi, Hiroaki
Takeuchi, Osamu
Kawai, Taro
Kaisho, Tsuneyasu
Sato, Shintaro
Sanjo, Hideki
Hoshino, Katsuaki
Takeda, Kiyoshi
Akira, Shizuo
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2000-12-07
Volume: 408
Issue: 6813
Pages: 740-745
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/35047123
OpenAlex: W1514540900
Cited by: 6,491
References: 33
Citations by year: 2026: 85 · 2025: 115 · 2024: 136 · 2023: 167 · 2022: 156 · 2021: 191 · 2020: 180 · 2019: 164 · 2018: 187 · 2017: 219 · 2016: 201 · 2015: 226 · 2014: 276 · 2013: 281 · 2012: 235
FWCI: 102.08
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: Japan Society for the Promotion of Science
Topics: Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords: TLR9, CpG, innate immunity, T helper 1 response, adjuvants, vaccination, dendritic cell maturation, macrophage cytokine production, self-DNA, TLR9-deficient mice
MeSH terms: Amino Acid Sequence, Animals, Antigens, Differentiation, Base Sequence, Cells, Cultured, Cloning, Molecular, Dendritic Cells, DNA-Binding Proteins, DNA, Bacterial, T-Lymphocytes, Helper-Inducer, Humans, Membrane Glycoproteins, Mice, Inbred C57BL, Molecular Sequence Data, Receptors, Cell Surface, Receptors, Immunologic, Dinucleoside Phosphates, Signal Transduction, Cytokines, Mutagenesis, Sequence Homology, Amino Acid, Drosophila Proteins, Adaptor Proteins, Signal Transducing, Toll-Like Receptors, Toll-Like Receptor 9, Mice, Myeloid Differentiation Factor 88

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