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

Human blood V gamma 9/V delta 2 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 V gamma 9/V delta 2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8). In turn, V gamma 9/V delta 2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha. 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 V gamma 9/V delta 2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1), and results in a TNF-alpha dependent proliferation of V gamma 9/V delta 2 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 gamma delta 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 V gamma 9/V delta 2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The gamma delta T cell-driven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of gamma delta T cells and TNF-alpha 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 gamma delta T cells in early infection and suggest novel diagnostic and therapeutic approaches.