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

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.

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

“…Not depicted, for the sake of clarity, are possible scenarios in which cd T-APCs or cd T cell-induced DCs present antigens locally to tissue-resident or newly arrived CD4 + and CD8 + T cells, or in which APC-like neutrophils enter the draining lymph node. Monocytes are critical for the activation and proliferation of Vc9/Vd2 T cells in response to neutrophil-released microbial compounds [9,10], and are thus likely to drive early inflammatory responses in acute microbial infections [60], which can be mimicked in vitro by providing soluble HMB-PP [61,62]. In addition, monocytes are also essential for Vc9/Vd2 T cell responses to aminobisphosphonates such as zoledronate by facilitating uptake of these compounds through endocytosis and intracellular accumulation of IPP [63][64][65].…”

“…Activated Vc9/Vd2 T cells in fact induce chemotaxis and phagocytosis of neutrophils [85,86], and in return microbial compounds released by neutrophils upon phagocytosis of different pathogens are sensed by Vc9/Vd2 T cells [9,10], suggesting an intimate crosstalk of the two cell types, typically leading to their mutual activation. However, recent supports also suggest that under certain conditions neutrophils may actually suppress Vc9/Vd2 T cell responses [87,88], indicative of a fine-tuned regulatory interplay between the two cell types depending on the microenvironment [89].…”

“…Davey et al [9] demonstrated a striking anti-apoptotic effect of Vc9/Vd2 T cells on human neutrophils that significantly extends the lifespan of cultured neutrophils. Over a period of 48 h these surviving neutrophils show signs of strong activation such as the presence of hypersegmented nuclei together with an upregulated surface expression of CD11b and CD66b and complete shedding of CD62L [10].…”

“…Vc9/Vd2 + cd T cells represent the major cd T cell subset in human peripheral blood where they typically comprise 1-5% in healthy adults [8]. In many microbial infections, Vc9/Vd2 T cells increase locally and/or systemically [9,10] and can reach in excess of 50% of all peripheral T cells within a matter of days [11], revealing a fundamental role of this unconventional T cell population in acute disease and suggesting their exploitation for diagnostic and therapeutic purposes [12][13][14]. Vc9/Vd2 T cells uniformly respond to a class of low molecular weight molecules often referred to as 'phosphoantigens' that represent metabolites of the isoprenoid biosynthesis, or synthetic analogs thereof.…”

Revisiting the protective and pathogenic roles of neutrophils: Ly‐6G is key!

“…Neutrophils can also facilitate the recruitment of Th2 cells in airway inflammatory responses [6]. In addition, neutrophils can be controlled by regulatory T cells or can interact with invariant natural killer T cells (iNKT cells), conventional NK cells or gd T cells to regulate or activate immune responses [27][28][29].…”