Human neutrophil clearance of bacterial pathogens triggers anti-microbial γδ T cell responses in early infection

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dc.contributor.authorDavey, Martin S.
dc.contributor.authorLin, Chan-Yu
dc.contributor.authorRoberts, Gareth W.
dc.contributor.authorHeuston, Sinéad
dc.contributor.authorBrown, Amanda C.
dc.contributor.authorChess, James A.
dc.contributor.authorToleman, Mark A.
dc.contributor.authorGahan, Cormac G.
dc.contributor.authorHill, Colin
dc.contributor.authorParish, Tanya
dc.contributor.authorWilliams, John D.
dc.contributor.authorDavies, Simon J.
dc.contributor.authorJohnson, David W.
dc.contributor.authorTopley, Nicholas
dc.contributor.authorMoser, Bernhard
dc.contributor.authorEberl, Matthias
dc.contributor.editorWherry, E. John
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderWelsh Assembly Governmenten
dc.contributor.funderBaxter Healthcare Corporation, United Statesen
dc.contributor.funderRoyal Society, United Kingdomen
dc.contributor.funderResearch Councils UK, United Kingdomen
dc.date.accessioned2012-12-12T11:52:48Z
dc.date.available2012-12-12T11:52:48Z
dc.date.copyright2011
dc.date.issued2011-05-12
dc.description.abstractHuman blood Vc9/Vd2 T cells, monocytes and neutrophils share a responsiveness toward inflammatory chemokines and are rapidly recruited to sites of infection. Studying their interaction in vitro and relating these findings to in vivo observations in patients may therefore provide crucial insight into inflammatory events. Our present data demonstrate that Vc9/Vd2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8). In turn, Vc9/Vd2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN)-c and tumor necrosis factor (TNF)-a. This response is dependent on the ability of these bacteria to produce the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), requires cell-cell contact of Vc9/Vd2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1), and results in a TNF-a dependent proliferation of Vc9/Vd2 T cells. The antibiotic fosmidomycin, which targets the HMB-PP biosynthesis pathway, not only has a direct antibacterial effect on most HMB-PP producing bacteria but also possesses rapid anti-inflammatory properties by inhibiting cd T cell responses in vitro. Patients with acute peritoneal-dialysis (PD)-associated bacterial peritonitis – characterized by an excessive influx of neutrophils and monocytes into the peritoneal cavity – show a selective activation of local Vc9/Vd2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The cd T celldriven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of cd T cells and TNF-a and detrimental clinical outcomes in infections caused by HMB-PP positive microorganisms. Taken together, our findings indicate a direct link between invading pathogens, neutrophils, monocytes and microbe-responsive cd T cells in early infection and suggest novel diagnostic and therapeutic approaches.en
dc.description.sponsorshipScience Foundation Ireland (SFI-CSET); Welsh Assembly Government (H07-03-18); Welsh Assembly Government (HA09-009); Baxter Healthcare Corporation, United States (Extramural Grant #08AP002); Royal Society, United Kingdom (Wolfson Research Merit Award); Research Councils UK, United Kingdom (Fellowship in Translational Research)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationDavey MS, Lin C-Y, Roberts GW, Heuston S, Brown AC, et al. (2011) Human Neutrophil Clearance of Bacterial Pathogens Triggers Anti-Microbial cd T Cell Responses in Early Infection. PLoS Pathog 7(5): e1002040. doi:10.1371/journal.ppat.1002040en
dc.identifier.doi10.1371/journal.ppat.1002040
dc.identifier.issn1553-7366
dc.identifier.issued5en
dc.identifier.journaltitlePLoS Pathogensen
dc.identifier.startpagee1002040en
dc.identifier.urihttps://hdl.handle.net/10468/850
dc.identifier.volume7en
dc.language.isoenen
dc.publisherPLOSen
dc.relation.urihttp://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1002040
dc.rights© 2011 Davey et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.rights.urihttp://creativecommons.org/licenses/by/2.5/en
dc.subjectNeutrophilen
dc.subjectChemokinesen
dc.subjectPhagocytosed Bacteriaen
dc.subjectFosmidomycinen
dc.subjectHMB-PPen
dc.subjectPeritonitisen
dc.titleHuman neutrophil clearance of bacterial pathogens triggers anti-microbial γδ T cell responses in early infectionen
dc.typeArticle (peer-reviewed)en
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