International Immunology Advance Access originally published online on May 25, 2006
International Immunology 2006 18(7):1115-1126; doi:10.1093/intimm/dxl046
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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
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