Abstract
Vγ9/Vδ2 T cells are a minor subset of T cells in human blood and differ from other T cells by their immediate responsiveness to microbes. We previously demonstrated that the primary target for Vγ9/Vδ2 T cells is (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), an essential metabolite produced by a large range of pathogens. Here we wished to study the consequence of this unique responsiveness in microbial infection. The majority of peripheral Vγ9/Vδ2 T cells shares migration properties with circulating monocytes, which explains the presence of these two distinct blood cell types in the inflammatory infiltrate at sites of infection and suggests that they synergize in anti-microbial immune responses. Our present findings demonstrate a rapid and HMB-PP-dependent crosstalk between Vγ9/Vδ2 T cells and autologous monocytes that results in the immediate production of inflammatory mediators including the cytokines interleukin (IL)-6, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and oncostatin M (OSM); the chemokines CCL2, CXCL8, and CXCL10; and TNF-related apoptosis-inducing ligand (TRAIL). Moreover, under these co-culture conditions monocytes differentiate within 18 hours into inflammatory dendritic cells (DCs) with antigen-presenting functions. Addition of further microbial stimuli (lipopolysaccharide, peptidoglycan) induces CCR7 and enables these inflammatory DCs to trigger the generation of CD4+ effector αβ T cells expressing IFN-γ and/or IL-17. Importantly, our in vitro model replicates the responsiveness to microbes of effluent cells from peritoneal dialysis (PD) patients and translates directly to episodes of acute PD-associated bacterial peritonitis, where Vγ9/Vδ2 T cell numbers and soluble inflammatory mediators are elevated in patients infected with HMB-PP-producing pathogens. Collectively, these findings suggest a direct link between invading pathogens, microbe-responsive γδ T cells, and monocytes in the inflammatory infiltrate, which plays a crucial role in the early response and the generation of microbe-specific immunity.
Highlights
The immune system has evolved to survey the body constantly for potentially hazardous structures
There is a paucity of data on Vc9/Vd2 T cells from anatomical locations other than blood and secondary lymphoid tissue, and information on the response of Vc9/Vd2 T cells in acute infection is especially sparse, not least due to the absence of hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP)-reactive cd T cells in small animal models [4,5,6,8]
Studies in severe combined immunodeficiency mice reconstituted with human peripheral blood mononuclear cells (PBMC) suggested that Vc9/Vd2 T cell may mediate rapid clearance of intraperitoneal infections, by enhancing monocyte-mediated killing of bacteria through production of interferon (IFN)-c and tumor necrosis factor (TNF)-a [26]
Summary
The immune system has evolved to survey the body constantly for potentially hazardous structures. Microbial signals comprise pathogen-associated molecular patterns (PAMPs) that are invariant among a broad range of organisms, allow self/non-self discrimination, and are detected by germline-encoded pattern recognition receptors [2,3]. By contrast to this innate immune recognition, the adaptive immune response is mediated via somatically rearranged and clonally distributed antigen receptors on B cells and ab T cells. Selection and peripheral amplification of public Vc9–Jc1.2 clonotypes during early childhood appears to ensure rapid, innate-like responses of Vc9/Vd2 T cells to invading pathogens in later life [12,13]
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