Human Neutrophil Clearance of Bacterial Pathogens Triggers Anti-Microbial γδ T Cell Responses in Early Infection

PLoS Pathogens

Colin Hill¹  Tanya Parish¹  Amanda C. Brown¹  Bernhard Moser²  John D. Williams³  James A. Chess³  Cormac G. M. Gahan⁴  Chan-Yu Lin⁴  Martin S. Davey⁴  Matthias Eberl⁴  Gareth W. Roberts⁵  Mark A. Toleman⁶  Nicholas Topley⁷  David W. Johnson⁸  Simon J. Davies⁹  Sinéad Heuston⁹ 

[1] Alimentary Pharmabiotic Centre and Department of Microbiology, University College Cork, Cork, Ireland;Australia and New Zealand Dialysis Transplant Registry, University of Adelaide, Adelaide, Australia;Centre for Immunology and Infectious Disease, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, United Kingdom;Department of Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, Cardiff, United Kingdom;Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan;Department of Nephrology, Morriston Hospital, Swansea, United Kingdom;Department of Nephrology, Princess Alexandra Hospital, University of Queensland, Brisbane, Australia;Department of Nephrology, University Hospital of North Staffordshire, Keele University, Stoke-on-Trent, United Kingdom;Institute of Nephrology, School of Medicine, Cardiff University, Cardiff, United Kingdom

关键词: T cells;    Neutrophils;    Monocytes;    Bacterial pathogens;    Inflammation;    Peritonitis;    Bacteria;    Pathogens;   

DOI  :  10.1371/journal.ppat.1002040

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY