International Immunology Advance Access originally published online on May 25, 2006
International Immunology 2006 18(7):1115-1126; doi:10.1093/intimm/dxl046
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Distinct indirect pathways govern human NK-cell activation by TLR-7 and TLR-8 agonists
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
Correspondence to: K. S. Gorski; E-mail: kgorski{at}mmm.com
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-
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- by purified NK cells suggesting indirect activation. IL-18 and IL-12p70 were primarily required for induction of IFN- 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- 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
Transmitting editor: G. Trinchieri
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  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., June 18, 2009; (2009) gkp525v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|