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

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

Research output: Contribution to journalArticlepeer-review

144 Scopus citations


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-γ 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-γ by purified NK cells suggesting indirect activation. IL-18 and IL-12p70 were primarily required for induction of IFN-γ 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-γ 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 mlM-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.

Original languageEnglish (US)
Pages (from-to)1115-1126
Number of pages12
JournalInternational Immunology
Issue number7
StatePublished - Jul 2006


  • Cytokines
  • Cytotoxicity
  • NK cells
  • Toll-like receptors


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