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* Centre d’Immunologie de Marseille-Luminy, Université de la Méditerranée, Institut National de la Santé et de la Recherche Médicale Unité, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6102, Case 906, Campus de Luminy, Marseille, France;
Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912;
Cincinnati Children’s Hospital Research Foundation, University of Cincinnati College of Medicine, Division of Molecular Immunology, Cincinnati, OH 45229;
University of Orléans and Centre National de la Recherche Scientifique Unité Mixte de Recherche 6218, Orléans, France;
¶ Department of Immunology, Scripps Research Institute, La Jolla, CA 92037; and
|| Hôpital de la Conception, Assistance Publique, Hôpitaux de Marseille, Marseille, France
Recent evidence suggests that NK cells require priming to display full effector activity. In this study, we demonstrate that IL-18 contributed to this phenomenon. IL-18 signaling-deficient NK cells were found to be unable to secrete IFN-
in response to ex vivo stimulation with IL-12. This was not due to a costimulatory role of IL-18, because blocking IL-18 signaling during the ex vivo stimulation with IL-12 did not alter IFN- production by wild-type NK cells. Rather, we demonstrate that IL-18 primes NK cells in vivo to produce IFN- upon subsequent stimulation with IL-12. Importantly, IL-12-induced IFN- transcription by NK cells was comparable in IL-18 signaling-deficient and -sufficient NK cells. This suggests that priming by IL-18 leads to an improved translation of IFN- mRNA. These results reveal a novel type of cooperation between IL-12 and IL-18 that requires the sequential action of these cytokines.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 The E.V. laboratory is supported by European Union (<<Allostem>>), Ligue Nationale contre le Cancer ("Equipe labelisée"), Agence Nationale de la Recherche, INSERM, CNRS, Ministère de l’Enseignement Supérieur et de la Recherche, and Institut Universitaire de France. This work was also supported by National Institutes of Health Grant AI058181 (to L.B.).
2 Address correspondence and reprint requests to Dr. Eric Vivier and Dr. Thierry Walzer, Centre d’Immunologie de Marseille-Luminy, Université de la Méditerranée, Institut National de la Santé et de la Recherche Médicale Unité, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6102, Case 906, Campus de Luminy, Marseille 13288, France. E-mail addresses: vivier{at}ciml.univ-mrs.fr and walzer{at}ciml.univ-mrs.fr
3 Abbreviations used in this paper: DC, dendritic cell; IRAK4, IL-1R-associated kinase 4; KO, knockout; LAK, lymphokine-activated killer; poly(I:C), polyinosinic:polycytidylic acid; TIR, TLR/IL-1R.
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