Skip Navigation



International Immunology Advance Access published online on May 25, 2006
International Immunology, doi:10.1093/intimm/dxl046
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow Supplementary Data
Right arrow All Versions of this Article:
18/7/1115    most recent
dxl046v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Gorski, K. S.
Right arrow Articles by Alkan, S. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gorski, K. S.
Right arrow Articles by Alkan, S. S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Japanese Society for Immunology. 2006. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org
Received January 19, 2006
Accepted April 21, 2006

Article

Distinct indirect pathways govern human NK-cell activation by TLR-7 and TLR-8 agonists

Kevin S. Gorski 1 *, Emily L. Waller 1, Jacqueline Bjornton-Severson 1, John A. Hanten 1, Christie L. Riter 1, William C. Kieper 1, Keith B. Gorden 1, Jeffrey S. Miller 2, John P. Vasilakos 1, Mark A. Tomai 1, and Sefik S. Alkan 1

1 3M Pharmaceuticals, Department of Pharmacology, 3M Center, 270-2S-06, St Paul, MN 55144, USA
2 Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN 55455, USA

* To whom correspondence should be addressed.
Kevin S. Gorski, E-mail: kgorski{at}mmm.com


  Abstract

NK cells limit the emergence of cancers and viral infections by surveillance of ‘missing-self’ and ‘induced-self’ ligands, and by direct recognition of pathogen-associated molecules. We examined individual roles for Toll-like receptors (TLRs)-7 and -8 in human NK-cell activation using synthetic, small molecule agonists of either TLR-7 (imiquimod and 3M-001), TLR-8 (3M-002) or both TLR-7/8 (3M-003 and R-848) for comparison with known ligands of TLR-2 to -9. Tracking cytokine production in PBMC initially revealed that a subset of TLR agonists including polyinosinic-polycytidylic acid (poly I:C), 3M-002, 3M-003, R-848 and single-stranded RNA trigger relatively high levels of IFN-{gamma} expression by NK cells. Isolated NK cells did not express TLR-7 or TLR-8. Unlike MALP-2 and poly I:C, 3M-001-3 did not induce expression of either CD69 or IFN-{gamma} by purified NK cells suggesting indirect activation. IL-18 and IL-12p70 were primarily required for induction of IFN-{gamma} by both synthetic and natural TLR-8 ligands, while type I IFN was required for induction of CD69 on NK cells by the TLR-7 agonist 3M-001. In addition to expression of IFN-{gamma} and CD69, relative induction of NK-cell cytotoxicity by TLR-7 and TLR-8 agonists was compared. Immune response modifiers (IRMs) with a TLR-8 agonist component (3M-002 and 3M-003) stimulated greater levels of K562 cytolysis than achieved with 3M-001 or IL-2 (1000 units ml-1). In vivo NK-cell cytotoxicity was also enhanced by R-848, but not in type I IFNR-deficient mice. We conclude that IRMs can modulate NK-cell function both in vitro and in vivo and that distinct indirect pathways control human NK-cell activation by TLR-7 and TLR-8 agonists.

Keywords: cytokines; cytotoxicity; NK cells; Toll-like receptors.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Immunol.Home page
C. Bourquin, L. Schmidt, A.-L. Lanz, B. Storch, C. Wurzenberger, D. Anz, N. Sandholzer, R. Mocikat, M. Berger, H. Poeck, et al.
Immunostimulatory RNA Oligonucleotides Induce an Effective Antitumoral NK Cell Response through the TLR7
J. Immunol., November 15, 2009; 183(10): 6078 - 6086.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. GenomicsHome page
P. Camateros, C. Kanagaratham, J. Henri, R. Sladek, T. J. Hudson, and D. Radzioch
Modulation of the allergic asthma transcriptome following resiquimod treatment
Physiol Genomics, August 7, 2009; 38(3): 303 - 318.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
C. D. Sadik, M. Bachmann, J. Pfeilschifter, and H. Muhl
Activation of interferon regulatory factor-3 via toll-like receptor 3 and immunomodulatory functions detected in A549 lung epithelial cells exposed to misplaced U1-snRNA
Nucleic Acids Res., August 1, 2009; 37(15): 5041 - 5056.
[Abstract] [Full Text] [PDF]

Home page
 CVIHome page
F. N. Toka, C. K. Nfon, H. Dawson, and W. T. Golde
Accessory-Cell-Mediated Activation of Porcine NK Cells by Toll-Like Receptor 7 (TLR7) and TLR8 Agonists
Clin. Vaccine Immunol., June 1, 2009; 16(6): 866 - 878.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
S. H. Kassim, N. K. Rajasagi, B. W. Ritz, S. B. Pruett, E. M. Gardner, R. Chervenak, and S. R. Jennings
Dendritic Cells Are Required for Optimal Activation of Natural Killer Functions following Primary Infection with Herpes Simplex Virus Type 1
J. Virol., April 1, 2009; 83(7): 3175 - 3186.
[Abstract] [Full Text] [PDF]

Home page
 The OncologistHome page
E. L. J. M. Smits, P. Ponsaerts, Z. N. Berneman, and V. F. I. Van Tendeloo
The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer Immunotherapy
Oncologist, August 1, 2008; 13(8): 859 - 875.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
T. Strowig, F. Brilot, and C. Munz
Noncytotoxic Functions of NK Cells: Direct Pathogen Restriction and Assistance to Adaptive Immunity
J. Immunol., June 15, 2008; 180(12): 7785 - 7791.
[Abstract] [Full Text] [PDF]

Home page
 J Clin PharmacolHome page
C. Astry, W. Birmachu, L. I. Harrison, and T.-C. Meng
Cutaneous Pharmacodynamics of a Toll-Like Receptor 7 Agonist, 852A, in Humans
J. Clin. Pharmacol., June 1, 2008; 48(6): 755 - 762.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
A. Forsbach, J.-G. Nemorin, C. Montino, C. Muller, U. Samulowitz, A. P. Vicari, M. Jurk, G. K. Mutwiri, A. M. Krieg, G. B. Lipford, et al.
Identification of RNA Sequence Motifs Stimulating Sequence-Specific TLR8-Dependent Immune Responses
J. Immunol., March 15, 2008; 180(6): 3729 - 3738.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. P. Gantier, S. Tong, M. A. Behlke, D. Xu, S. Phipps, P. S. Foster, and B. R. G. Williams
TLR7 Is Involved in Sequence-Specific Sensing of Single-Stranded RNAs in Human Macrophages
J. Immunol., February 15, 2008; 180(4): 2117 - 2124.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
R. Dummer, A. Hauschild, J. C. Becker, J.-J. Grob, D. Schadendorf, V. Tebbs, J. Skalsky, K. C. Kaehler, S. Moosbauer, R. Clark, et al.
An Exploratory Study of Systemic Administration of the Toll-like Receptor-7 Agonist 852A in Patients with Refractory Metastatic Melanoma
Clin. Cancer Res., February 1, 2008; 14(3): 856 - 864.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
A. Z. Dudek, C. Yunis, L. I. Harrison, S. Kumar, R. Hawkinson, S. Cooley, J. P. Vasilakos, K. S. Gorski, and J. S. Miller
First in Human Phase I Trial of 852A, a Novel Systemic Toll-like Receptor 7 Agonist, to Activate Innate Immune Responses in Patients with Advanced Cancer
Clin. Cancer Res., December 1, 2007; 13(23): 7119 - 7125.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. V. Girart, M. B. Fuertes, C. I. Domaica, L. E. Rossi, and N. W. Zwirner
Engagement of TLR3, TLR7, and NKG2D Regulate IFN-{gamma} Secretion but Not NKG2D-Mediated Cytotoxicity by Human NK Cells Stimulated with Suboptimal Doses of IL-12
J. Immunol., September 15, 2007; 179(6): 3472 - 3479.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
A. Meier, G. Alter, N. Frahm, H. Sidhu, B. Li, A. Bagchi, N. Teigen, H. Streeck, H.-J. Stellbrink, J. Hellman, et al.
MyD88-Dependent Immune Activation Mediated by Human Immunodeficiency Virus Type 1-Encoded Toll-Like Receptor Ligands
J. Virol., August 1, 2007; 81(15): 8180 - 8191.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.