{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T15:33:49Z","timestamp":1791214429269,"version":"4.1.0"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2008,11,1]],"date-time":"2008-11-01T00:00:00Z","timestamp":1225497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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-\u03b3, 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-\u03b3 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-\u03b3 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-\u03b3 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 \u201chelpers\u201d in bacterial infection.<\/jats:p>","DOI":"10.4049\/jimmunol.181.10.7121","type":"journal-article","created":{"date-parts":[[2014,4,18]],"date-time":"2014-04-18T23:00:36Z","timestamp":1397862036000},"page":"7121-7130","source":"Crossref","is-referenced-by-count":124,"title":["A Novel Role for Neutrophils As Critical Activators of NK Cells"],"prefix":"10.1093","volume":"181","author":[{"given":"Roman","family":"Sp\u00f6rri","sequence":"first","affiliation":[{"name":"ETH Zurich, Institute for Microbiology , Z\u00fcrich,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Joller","sequence":"additional","affiliation":[{"name":"ETH Zurich, Institute for Microbiology , Z\u00fcrich,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hubert","family":"Hilbi","sequence":"additional","affiliation":[{"name":"ETH Zurich, Institute for Microbiology , Z\u00fcrich,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Oxenius","sequence":"additional","affiliation":[{"name":"ETH Zurich, Institute for Microbiology , Z\u00fcrich,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2008,11,15]]},"reference":[{"key":"2025032700372389100_R1","first-page":"104","article-title":"Disorders of neutrophil number and function","volume-title":"Hematology Am. Soc. Hematol. Educ. Prog.","year":"2006"},{"key":"2025032700372389100_R2","first-page":"197","article-title":"How neutrophils kill microbes","volume-title":"Annu. Rev. Immunol.","year":"2005"},{"key":"2025032700372389100_R3","first-page":"1329","article-title":"Mechanisms of pathogenesis: evasion of killing by polymorphonuclear leukocytes","volume-title":"Microbes Infect.","year":"2003"},{"key":"2025032700372389100_R4","first-page":"386","article-title":"Interaction of the Legionnaires\u2019 disease bacterium (Legionella pneumophila) with human phagocytes. I: L. pneumophila resists killing by polymorphonuclear leukocytes, antibody, and complement","volume-title":"J. Exp. Med.","year":"1981"},{"key":"2025032700372389100_R5","first-page":"510","article-title":"The contribution of human neutrophils and serum to host defense against Legionella micdadei","volume-title":"J. Infect. Dis.","year":"1983"},{"key":"2025032700372389100_R6","first-page":"625","article-title":"Risk factors for nosocomial Legionella pneumophila pneumonia","volume-title":"Am. J. Respir. Crit. Care Med.","year":"1994"},{"key":"2025032700372389100_R7","first-page":"68","article-title":"Fatal Legionella pneumonitis in a neutropenic leukemic child","volume-title":"Pediatr. Infect. Dis. J.","year":"1987"},{"key":"2025032700372389100_R8","first-page":"81","article-title":"Legionnaires\u2019 disease in patients with cancer","volume-title":"Med. Pediatr. Oncol.","year":"1986"},{"key":"2025032700372389100_R9","first-page":"105","article-title":"Effects of polymorphonuclear leucocyte depletion on the pathogenesis of experimental Legionnaires\u2019 disease","volume-title":"Br. J. Exp. Pathol.","year":"1988"},{"key":"2025032700372389100_R10","first-page":"3355","article-title":"Early recruitment of neutrophils determines subsequent T1\/T2 host responses in a murine model of Legionella pneumophila pneumonia","volume-title":"J. Immunol.","year":"2001"},{"key":"2025032700372389100_R11","first-page":"1537","article-title":"Replicative Legionella pneumophila lung infection in intratracheally inoculated A\/J mice: a murine model of human Legionnaires\u2019 disease","volume-title":"Am. J. Pathol.","year":"1994"},{"key":"2025032700372389100_R12","first-page":"6162","article-title":"MyD88-dependent IFN-\u03b3 production by NK cells is key for control of Legionella pneumophila infection","volume-title":"J. Immunol.","year":"2006"},{"key":"2025032700372389100_R13","first-page":"372","article-title":"Effector proteins translocated by Legionella pneumophila: strength in numbers","volume-title":"Trends Microbiol.","year":"2007"},{"key":"2025032700372389100_R14","first-page":"344","article-title":"The pathology of Legionnaires\u2019 disease: fourteen fatal cases from the 1977 outbreak in Vermont","volume-title":"Arch. Pathol. Lab. Med.","year":"1978"},{"key":"2025032700372389100_R15","first-page":"3166","article-title":"Maturation of the Legionella pneumophila-containing phagosome into a phagolysosome within \u03b3 interferon-activated macrophages","volume-title":"Infect. Immun.","year":"2005"},{"key":"2025032700372389100_R16","first-page":"64","article-title":"Purification of a factor which provides a costimulatory signal for \u03b3 interferon production","volume-title":"Infect. Immun.","year":"1993"},{"key":"2025032700372389100_R17","first-page":"112","article-title":"Close encounters of different kinds: dendritic cells and NK cells take centre stage","volume-title":"Nat. Rev. Immunol.","year":"2005"},{"key":"2025032700372389100_R18","first-page":"2366","article-title":"Dendritic cells mediate NK cell help for Th1 and CTL responses: two-signal requirement for the induction of NK cell helper function","volume-title":"J. Immunol.","year":"2003"},{"key":"2025032700372389100_R19","first-page":"3325","article-title":"MyD88-dependent responses involving Toll-like receptor 2 are important for protection and clearance of Legionella pneumophila in a mouse model of Legionnaires\u2019 disease","volume-title":"Infect. Immun.","year":"2006"},{"key":"2025032700372389100_R20","first-page":"305","article-title":"Role of Toll-like receptor 2 in recognition of Legionella pneumophila in a murine pneumonia model","volume-title":"J. Med. Microbiol.","year":"2007"},{"key":"2025032700372389100_R21","first-page":"1693","article-title":"Myeloid differentiation primary response gene (88)- and Toll-like receptor 2-deficient mice are susceptible to infection with aerosolized Legionella pneumophila","volume-title":"J. Infect. Dis.","year":"2006"},{"key":"2025032700372389100_R22","first-page":"146","article-title":"Role of Toll-like receptor 9 in Legionella pneumophila-induced interleukin-12 p40 production in bone marrow-derived dendritic cells and macrophages from permissive and nonpermissive mice","volume-title":"Infect. Immun.","year":"2007"},{"key":"2025032700372389100_R23","first-page":"2895","article-title":"TLR9 regulates lung macrophage phenotype and host immunity in murine Legionella pneumonia","volume-title":"Infect. Immun.","year":"2008"},{"key":"2025032700372389100_R24","first-page":"143","article-title":"Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function","volume-title":"Immunity","year":"1998"},{"key":"2025032700372389100_R25","first-page":"5361","article-title":"Identification of Legionella pneumophila genes required for growth within and killing of human macrophages","volume-title":"Infect. Immun.","year":"1993"},{"key":"2025032700372389100_R26","first-page":"133","article-title":"Interleukin-12 and the regulation of innate resistance and adaptive immunity","volume-title":"Nat. Rev. Immunol.","year":"2003"},{"key":"2025032700372389100_R27","first-page":"65","article-title":"In vivo regulation of replicative Legionella pneumophila lung infection by endogenous interleukin-12","volume-title":"Infect. Immun.","year":"1998"},{"key":"2025032700372389100_R28","first-page":"6567","article-title":"Immunomodulatory role of endogenous interleukin-18 in \u03b3 interferon-mediated resolution of replicative Legionella pneumophila lung infection","volume-title":"Infect. Immun.","year":"2000"},{"key":"2025032700372389100_R29","first-page":"88","article-title":"Cloning of a new cytokine that induces IFN-\u03b3 production by T cells","volume-title":"Nature","year":"1995"},{"key":"2025032700372389100_R30","first-page":"206","article-title":"Activation of interferon-\u03b3 inducing factor mediated by interleukin-1\u03b2 converting enzyme","volume-title":"Science","year":"1997"},{"key":"2025032700372389100_R31","first-page":"619","article-title":"Caspase-1 processes IFN-\u03b3-inducing factor and regulates LPS-induced IFN-\u03b3 production","volume-title":"Nature","year":"1997"},{"key":"2025032700372389100_R32","first-page":"39","article-title":"Intracellular pattern recognition receptors in the host response","volume-title":"Nature","year":"2006"},{"key":"2025032700372389100_R33","first-page":"318","article-title":"The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection","volume-title":"Nat. Immunol.","year":"2006"},{"key":"2025032700372389100_R34","first-page":"72","article-title":"Human phagocytes lack the ability to kill Mycobacterium gordonae, a non-pathogenic mycobacteria","volume-title":"Immunol. Lett.","year":"2008"},{"key":"2025032700372389100_R35","first-page":"5407","article-title":"Gr-1high polymorphonuclear leukocytes and NK cells act via IL-15 to clear intracellular Haemophilus influenzae in experimental murine peritonitis and pneumonia","volume-title":"J. Immunol.","year":"2007"},{"key":"2025032700372389100_R36","first-page":"722","article-title":"Expression and alternative processing of IL-18 in human neutrophils","volume-title":"Eur. J. Immunol.","year":"2006"},{"key":"2025032700372389100_R37","first-page":"3373","article-title":"IL-15 mediates antigen-induced neutrophil migration by triggering IL-18 production","volume-title":"Eur. J. Immunol.","year":"2007"},{"key":"2025032700372389100_R38","first-page":"4515","article-title":"Rapid recruitment of neutrophils containing prestored IL-12 during microbial infection","volume-title":"J. Immunol.","year":"2000"},{"key":"2025032700372389100_R39","first-page":"7369","article-title":"Human polymorphonuclear leukocytes produce IL-12, TNF-\u03b1, and the chemokines macrophage-inflammatory protein-1 \u03b1 and -1 \u03b2 in response to Toxoplasma gondii antigens","volume-title":"J. Immunol.","year":"1999"},{"key":"2025032700372389100_R40","first-page":"577","article-title":"Neutrophils play a protective nonphagocytic role in systemic Mycobacterium tuberculosis infection of mice","volume-title":"Infect. Immun.","year":"2000"},{"key":"2025032700372389100_R41","first-page":"2585","article-title":"Role of interleukin-18 (IL-18) in mycobacterial infection in IL-18-gene-disrupted mice","volume-title":"Infect. Immun.","year":"1999"},{"key":"2025032700372389100_R42","first-page":"213","article-title":"Interleukin-18","volume-title":"J. Leukocyte Biol.","year":"2003"},{"key":"2025032700372389100_R43","first-page":"99","article-title":"A critical role for neutrophils in resistance to experimental infection with Burkholderia pseudomallei","volume-title":"J. Infect. Dis.","year":"2007"},{"key":"2025032700372389100_R44","first-page":"3291","article-title":"Down-regulation of human natural killer activity against tumors by the neutrophil myeloperoxidase system and hydrogen peroxide","volume-title":"J. Immunol.","year":"1984"},{"key":"2025032700372389100_R45","first-page":"876","article-title":"Suppression of natural killing in vitro by monocytes and polymorphonuclear leukocytes: requirement for reactive metabolites of oxygen","volume-title":"J. Clin. Invest.","year":"1982"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/181\/10\/7121\/62580173\/8094.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/181\/10\/7121\/62580173\/8094.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,29]],"date-time":"2025-03-29T22:41:26Z","timestamp":1743288086000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/181\/10\/7121\/8007839"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,11]]},"references-count":45,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2008,11,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.181.10.7121","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"value":"1550-6606","type":"electronic"},{"value":"0022-1767","type":"print"}],"subject":[],"published-other":{"date-parts":[[2008,11]]},"published":{"date-parts":[[2008,11]]}}}