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The Journal of Immunology, 2001, 167: 3555-3558.
Copyright © 2001 by The American Association of Immunologists

Cutting Edge

Cutting Edge: Role of Toll-Like Receptor 9 in CpG DNA-Induced Activation of Human Cells1

Fumihiko Takeshita2,3, Cynthia A. Leifer2, Ihsan Gursel, Ken J. Ishii, Saoko Takeshita, Mayda Gursel and Dennis M. Klinman4

Section of Retroviral Immunology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892

Unmethylated CpG motifs present in bacterial DNA stimulate a rapid and robust innate immune response. Human cell lines and PBMC that recognize CpG DNA express membrane-bound human Toll-like receptor 9 (hTLR9). Cells that are not responsive to CpG DNA become responsive when transfected with hTLR9. Expression of hTLR9 dramatically increases uptake of CpG (but not control) DNA into endocytic vesicles. Upon cell stimulation, hTLR9 and CpG DNA are found in the same endocytic vesicles. Cells expressing hTLR9 are stimulated by CpG motifs that are active in primates but not rodents, suggesting that evolutionary divergence between TLR9 molecules underlies species-specific differences in the recognition of bacterial DNA. These findings indicate that hTLR9 plays a critical role in the CpG DNA-mediated activation of human cells.




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H. Xu, H. An, Y. Yu, M. Zhang, R. Qi, and X. Cao
Ras Participates in CpG Oligodeoxynucleotide Signaling through Association with Toll-like Receptor 9 and Promotion of Interleukin-1 Receptor-associated Kinase/Tumor Necrosis Factor Receptor-associated Factor 6 Complex Formation in Macrophages
J. Biol. Chem., September 19, 2003; 278(38): 36334 - 36340.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
I. Gursel, M. Gursel, H. Yamada, K. J. Ishii, F. Takeshita, and D. M. Klinman
Repetitive Elements in Mammalian Telomeres Suppress Bacterial DNA-Induced Immune Activation
J. Immunol., August 1, 2003; 171(3): 1393 - 1400.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
L.-Y. Huang, J. Aliberti, C. A. Leifer, D. M. Segal, A. Sher, D. T. Golenbock, and B. Golding
Heat-Killed Brucella abortus Induces TNF and IL-12p40 by Distinct MyD88-Dependent Pathways: TNF, Unlike IL-12p40 Secretion, Is Toll-Like Receptor 2 Dependent
J. Immunol., August 1, 2003; 171(3): 1441 - 1446.
[Abstract] [Full Text] [PDF]

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 BloodHome page
E. Bourke, D. Bosisio, J. Golay, N. Polentarutti, and A. Mantovani
The toll-like receptor repertoire of human B lymphocytes: inducible and selective expression of TLR9 and TLR10 in normal and transformed cells
Blood, August 1, 2003; 102(3): 956 - 963.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
T. J. Kemp, B. D. Elzey, and T. S. Griffith
Plasmacytoid Dendritic Cell-Derived IFN-{alpha} Induces TNF-Related Apoptosis-Inducing Ligand/Apo-2L-Mediated Antitumor Activity by Human Monocytes Following CpG Oligodeoxynucleotide Stimulation
J. Immunol., July 1, 2003; 171(1): 212 - 218.
[Abstract] [Full Text] [PDF]

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 BloodHome page
N. L. Bernasconi, N. Onai, and A. Lanzavecchia
A role for Toll-like receptors in acquired immunity: up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells
Blood, June 1, 2003; 101(11): 4500 - 4504.
[Abstract] [Full Text] [PDF]

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 J. Leukoc. Biol.Home page
U. Kumaraguru, C. D. Pack, and B. T. Rouse
Toll-like receptor ligand links innate and adaptive immune responses by the production of heat-shock proteins
J. Leukoc. Biol., May 1, 2003; 73(5): 574 - 583.
[Abstract] [Full Text] [PDF]

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 Int ImmunolHome page
A.-K. Yi, J.-G. Yoon, and A. M. Krieg
Convergence of CpG DNA- and BCR-mediated signals at the c-Jun N-terminal kinase and NF-{kappa}B activation pathways: regulation by mitogen-activated protein kinases
Int. Immunol., May 1, 2003; 15(5): 577 - 591.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
D. Verthelyi, M. Gursel, R. T. Kenney, J. D. Lifson, S. Liu, J. Mican, and D. M. Klinman
CpG Oligodeoxynucleotides Protect Normal and SIV-Infected Macaques from Leishmania Infection
J. Immunol., May 1, 2003; 170(9): 4717 - 4723.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
S. E. Blackwell and A. M. Krieg
CpG-A-Induced Monocyte IFN-{gamma}-Inducible Protein-10 Production Is Regulated by Plasmacytoid Dendritic Cell-Derived IFN-{alpha}
J. Immunol., April 15, 2003; 170(8): 4061 - 4068.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
H. Hemmi, T. Kaisho, K. Takeda, and S. Akira
The Roles of Toll-Like Receptor 9, MyD88, and DNA-Dependent Protein Kinase Catalytic Subunit in the Effects of Two Distinct CpG DNAs on Dendritic Cell Subsets
J. Immunol., March 15, 2003; 170(6): 3059 - 3064.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
K. Sano, H. Shirota, T. Terui, T. Hattori, and G. Tamura
Oligodeoxynucleotides Without CpG Motifs Work as Adjuvant for the Induction of Th2 Differentiation in a Sequence-Independent Manner
J. Immunol., March 1, 2003; 170(5): 2367 - 2373.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
J. E. Butler, P. Weber, M. Sinkora, D. Baker, A. Schoenherr, B. Mayer, and D. Francis
Antibody Repertoire Development in Fetal and Neonatal Piglets. VIII. Colonization Is Required for Newborn Piglets to Make Serum Antibodies to T-Dependent and Type 2 T-Independent Antigens
J. Immunol., December 15, 2002; 169(12): 6822 - 6830.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
H. Yamada, I. Gursel, F. Takeshita, J. Conover, K. J. Ishii, M. Gursel, S. Takeshita, and D. M. Klinman
Effect of Suppressive DNA on CpG-Induced Immune Activation
J. Immunol., November 15, 2002; 169(10): 5590 - 5594.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Cell Mol. Bio.Home page
S. Becker, M. J. Fenton, and J. M. Soukup
Involvement of Microbial Components and Toll-like Receptors 2 And 4 in Cytokine Responses to Air Pollution Particles
Am. J. Respir. Cell Mol. Biol., November 1, 2002; 27(5): 611 - 618.
[Abstract] [Full Text] [PDF]

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 J. Virol.Home page
R. B. Pyles, D. Higgins, C. Chalk, A. Zalar, J. Eiden, C. Brown, G. Van Nest, and L. R. Stanberry
Use of Immunostimulatory Sequence-Containing Oligonucleotides as Topical Therapy for Genital Herpes Simplex Virus Type 2 Infection
J. Virol., October 11, 2002; 76(22): 11387 - 11396.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
S. S. Mambula, K. Sau, P. Henneke, D. T. Golenbock, and S. M. Levitz
Toll-like Receptor (TLR) Signaling in Response to Aspergillus fumigatus
J. Biol. Chem., October 11, 2002; 277(42): 39320 - 39326.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
K. Heckelsmiller, K. Rall, S. Beck, A. Schlamp, J. Seiderer, B. Jahrsdorfer, A. Krug, S. Rothenfusser, S. Endres, and G. Hartmann
Peritumoral CpG DNA Elicits a Coordinated Response of CD8 T Cells and Innate Effectors to Cure Established Tumors in a Murine Colon Carcinoma Model
J. Immunol., October 1, 2002; 169(7): 3892 - 3899.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
J. Jung, A.-K. Yi, X. Zhang, J. Choe, L. Li, and Y. S. Choi
Distinct Response of Human B Cell Subpopulations in Recognition of an Innate Immune Signal, CpG DNA
J. Immunol., September 1, 2002; 169(5): 2368 - 2373.
[Abstract] [Full Text] [PDF]

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 JEMHome page
K. J. Ishii, F. Takeshita, I. Gursel, M. Gursel, J. Conover, A. Nussenzweig, and D. M. Klinman
Potential Role of Phosphatidylinositol 3 Kinase, rather than DNA-dependent Protein Kinase, in CpG DNA-induced Immune Activation
J. Exp. Med., July 15, 2002; 196(2): 269 - 274.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
M. Zheng, D. M. Klinman, M. Gierynska, and B. T. Rouse
DNA containing CpG motifs induces angiogenesis
PNAS, June 25, 2002; 99(13): 8944 - 8949.
[Abstract] [Full Text] [PDF]

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 Infect. Immun.Home page
A. Campos-Neto, J. R. Webb, K. Greeson, R. N. Coler, Y. A. W. Skeiky, and S. G. Reed
Vaccination with Plasmid DNA Encoding TSA/LmSTI1 Leishmanial Fusion Proteins Confers Protection against Leishmania major Infection in Susceptible BALB/c Mice
Infect. Immun., June 1, 2002; 70(6): 2828 - 2836.
[Abstract] [Full Text] [PDF]

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 J. Leukoc. Biol.Home page
M. Gursel, D. Verthelyi, I. Gursel, K. J. Ishii, and D. M. Klinman
Differential and competitive activation of human immune cells by distinct classes of CpG oligodeoxynucleotide
J. Leukoc. Biol., May 1, 2002; 71(5): 813 - 820.
[Abstract] [Full Text] [PDF]

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 Nucleic Acids ResHome page
D. Yu, E. R. Kandimalla, Q. Zhao, Y. Cong, and S. Agrawal
Immunostimulatory properties of phosphorothioate CpG DNA containing both 3'-5'- and 2'-5'-internucleotide linkages
Nucleic Acids Res., April 1, 2002; 30(7): 1613 - 1619.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
D. Verthelyi, R. T. Kenney, R. A. Seder, A. A. Gam, B. Friedag, and D. M. Klinman
CpG Oligodeoxynucleotides as Vaccine Adjuvants in Primates
J. Immunol., February 15, 2002; 168(4): 1659 - 1663.
[Abstract] [Full Text] [PDF]


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