Vgamma9/Vdelta2 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 Vgamma9/Vdelta2 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 Vgamma9/Vdelta2 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 Vgamma9/Vdelta2 T cells and autologous monocytes that results in the immediate production of inflammatory mediators including the
cytokines interleukin (IL)-6,
interferon (IFN)-gamma,
tumor necrosis factor (
TNF)-alpha, 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 alphabeta T cells expressing IFN-gamma 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 Vgamma9/Vdelta2 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 gammadelta T cells, and monocytes in the inflammatory infiltrate, which plays a crucial role in the early response and the generation of microbe-specific immunity.