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

Davey, Martin S., Lin, Chan-Yu, Roberts, Gareth W., Heuston, Sinead, Brown, Amanda C., Chess, James A., Toleman, Mark A., Gahan, Cormac G. M., Hill, Colin, Parish, Tanya, Williams, John D., Davies, Simon J., Johnson, David W., Topley, Nicholas, Moser, Bernhard and Eberl, Matthias (2011) Human neutrophil clearance of bacterial pathogens triggers anti-microbial γδ T cell responses in early infection. PLoS Pathogens, 7 5: . doi:10.1371/journal.ppat.1002040

Author Davey, Martin S.
Lin, Chan-Yu
Roberts, Gareth W.
Heuston, Sinead
Brown, Amanda C.
Chess, James A.
Toleman, Mark A.
Gahan, Cormac G. M.
Hill, Colin
Parish, Tanya
Williams, John D.
Davies, Simon J.
Johnson, David W.
Topley, Nicholas
Moser, Bernhard
Eberl, Matthias
Title Human neutrophil clearance of bacterial pathogens triggers anti-microbial γδ T cell responses in early infection
Journal name PLoS Pathogens   Check publisher's open access policy
ISSN 1553-7366
Publication date 2011-05
Sub-type Article (original research)
DOI 10.1371/journal.ppat.1002040
Open Access Status DOI
Volume 7
Issue 5
Total pages 14
Place of publication San Francisco, United States
Publisher Public Library of Science
Language eng
Formatted abstract
Human blood Vγ9/Vδ2 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 Vγ9/Vδ2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8). In turn, Vγ9/Vδ2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN)-γ and tumor necrosis factor (TNF)-α. 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 Vγ9/Vδ2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1), and results in a TNF-α dependent proliferation of Vγ9/Vδ2 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 γδ 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 Vγ9/Vδ2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The γδ T cell-driven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of γδ T cells and TNF-α 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 γδ T cells in early infection and suggest novel diagnostic and therapeutic approaches.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ
Additional Notes Article number e1002040

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 52 times in Thomson Reuters Web of Science Article | Citations
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