A Rapid Crosstalk of Human γδ T Cells and Monocytes Drives the Acute Inflammation in Bacterial Infections

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.

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

“…Our own research demonstrated that HMB-PP activated Vc9/Vd2 T cells trigger monocyte survival and activation in a highly sensitive and dose-dependent manner. These effects are still measurable at HMB-PP concentrations of down to 0.1 nM and ratios of up to 500 monocytes per Vc9/Vd2 T cells, and are thus likely to be of physiological relevance at the site of inflammation [61]. Of note, overactivation by Vc9/Vd2 T cells may also induce apoptosis of monocytes [69].…”

“…Most importantly, Vc9/Vd2 T cell-primed monocytes lose expression of CD14 and upregulate a whole set of APC markers, most notably CD40, CD86 and HLA-DR (Fig. 1), and also express DC-related markers such as CD83 and CD209, thereby acquiring a phenotype reminiscent of inflammatory DCs [61].While Vc9/Vd2 T cells are typically portrayed as pro-inflammatory [70] they nevertheless co-express factors such as . Indeed, most effects of Vc9/Vd2 T cells on monocytes are largely mediated via IFN-c and TNF-a as well as GM-CSF, yet IL-4 may make an additional contribution to shaping the phenotype and function of Vc9/Vd2 T cell-triggered inflammatory DCs [61].…”

“…1), and also express DC-related markers such as CD83 and CD209, thereby acquiring a phenotype reminiscent of inflammatory DCs [61].…”

“…Of note, the induction of CCR7 appears to require the presence of further microbial compounds such as LPS and peptidoglycan [[61]; B.M. and M.E, unpublished], suggesting a complex two-step differentiation and maturation process depending on a variety of microbial and environmental cues.In functional assays, Vc9/Vd2 T cell-primed monocytes present bacterial proteins or superantigens to autologous CD4 + T cells, typically resulting in the induction of IFN-c secreting CD4 + T cells [61]. However, Vc9/Vd2 T cell-primed monocytes exposed to microbial compounds such as LPS or peptidoglycan readily induce IL-17 secreting CD4 + T cells, indicating that the prevailing conditions in the local microenvironment may eventually dictate the outcome of such interactions and affect the balance between Th1 and Th17 dominated responses [60].…”

γδ-T cells: an unpolished sword in human anti-infection immunity

“…111 The contribution of cd-T cells to adaptive immunity goes beyond their APC function mentioned above. For example, cd-T cells are capable of inducing the maturation of DCs, 67 facilitating the development of ab-T cells, 13,112 killing regulatory T cells (Tregs) 113,114 and migrating into the secondary lymphoid tissues and acting as follicular B helper T cells to promote antibody production. 115,116 Moreover, cd-T cells can compete with ab-T cells for growth factors such as IL-15 and thus modify the adaptive immune response.…”