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A Novel Role for Neutrophils As Critical Activators of NK Cells¹

ETH Zurich, Institute for Microbiology, Zürich, Switzerland

Neutrophils are essential players in innate immune responses to bacterial infection. Despite the striking resistance of Legionella pneumophila (Lpn) to bactericidal neutrophil function, neutrophil granulocytes are important effectors in the resolution of legionellosis. Indeed, mice depleted of neutrophils were unable to clear Lpn due to a lack of the critical cytokine IFN-, which is produced by NK cells. We demonstrate that this can be ascribed to a previously unappreciated role of neutrophils as major NK cell activators. In response to Lpn infection, neutrophils activate caspase-1 and produce mature IL-18, which is indispensable for the activation of NK cells. Furthermore, we show that the IL-12p70 response in Lpn-infected neutropenic mice is also severely reduced and that the Lpn-induced IFN- production by NK cells is strictly dependent on IL-12. However, since dendritic cells, and not neutrophils, are the source of Lpn-induced IL-12, its paucity is a consequence of the absence of IFN- produced by NK cells rather than the absence of neutrophils per se. Therefore, neutrophil-derived IL-18, in combination with dendritic cell-produced IL-12, triggers IFN- synthesis in NK cells in Lpn-infected mice. We propose a novel central role for neutrophils as essential IL-18 producers and hence NK cell "helpers" in bacterial infection.

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 This work was supported by the Roche Research Fund for Biology, the Bonizzi-Theler Stiftung, the Gebert-Rüf-Stiftung, the Swiss National Science Foundation, the Vontobel Foundation, and by UBS AG on behalf of a client.

² Address correspondence and reprint requests to Dr. Roman Spörri, ETH Zurich Institute for Microbiology, Wolfgang-Pauli Strasse 10, 8093 Zurich, Switzerland. E-mail address: roman.spoerri{at}micro.biol.ethz.ch

³ Abbreviations used in this paper: Lpn, Legionella pneumophila; DC, dendritic cell; WT, wild type; BM, bone marrow; int, intermediate.

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