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

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

Publisher： Oxford University Press

ISSN： 1460-2377

Source： International Immunology, Vol.18, Iss.7, 2006-07, pp. : 1115-1126

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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- 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.