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


: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.


Int Immunol


International immunology


Gorski KS,Waller EL,Bjornton-Severson J,Hanten JA,Riter CL,Kieper WC,Gorden KB,Miller JS,Vasilakos JP,Tomai MA,Alkan SS




Has Abstract


2006-07-01 00:00:00














  • Vaccination of the Leishmania major susceptible BALB/c mouse. I. The precise selection of peptide determinant influences CD4+ T cell subset expression.

    abstract::BALB/c mice are susceptible to cutaneous leishmaniasis upon infection with Leishmania major while C57BL/6 are not. There is a major promastigote surface protease (PSP or gp63) which is available in both native and recombinant forms, and for which the primary amino acid sequence is known. Immunization with PSP has been...

    journal_title:International immunology

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    journal_title:International immunology

    pub_type: 杂志文章,评审


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    journal_title:International immunology

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    pub_type: 杂志文章


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    journal_title:International immunology

    pub_type: 杂志文章,评审


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    journal_title:International immunology

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    pub_type: 杂志文章


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    journal_title:International immunology

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    pub_type: 杂志文章


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    journal_title:International immunology

    pub_type: 杂志文章


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    journal_title:International immunology

    pub_type: 杂志文章


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    journal_title:International immunology

    pub_type: 杂志文章


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    journal_title:International immunology

    pub_type: 杂志文章


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    journal_title:International immunology

    pub_type: 杂志文章


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