Peripheral blood monocytes are responsible for γδ T cell activation induced by zoledronic acid through accumulation of IPP/DMAPP

Abstract

SummaryNitrogen-containing bisphosphonates indirectly activate Vc9Vd2 T cells through inhibition of farnesyl pyrophosphate synthase and intracellular accumulation of isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), but the cells responsible for Vc9Vd2 T cell activation through IPP/DMAPP accumulation are unknown. Treatment of human peripheral blood mononuclear cells (PBMCs) with a pharmacologically relevant concentration of zoledronic acid induced accumulation of IPP/DMAPP selectively in monocytes, which correlated with efficient drug uptake by these cells. Furthermore, zoledronic acid-pulsed monocytes triggered activation of cd T cells in a cell contact-dependent manner. These observations identify monocytes as the cell type directly affected by bisphosphonates responsible for Vc9Vd2 T cell activation.

Essential Requirements of Zoledronate-Induced Cytokine and γδ T Cell Proliferative Responses

“…Thus, zoledronate rapidly accumulates in monocytes. However, a 2.5-fold increase in IFN-g (from 10 to 25 pg/ml) and a 2.1-fold expansion of Vd2 T cells within 7 d, induced by zoledronate-treated monocytes and reported in the same study (20), does not convincingly demonstrate the importance of monocytes as a source of IPP. Rather, results from our study emphasize the role of monocytes as a source of IL-18.…”

“…The potent response of gd T cells in the complete absence of accessory cells, including monocytes, suggested that gd T cells can also take up zoledronate and produce sufficient amounts of IPP, a property that previously was attributed to monocytes only (20). However, Moser and colleagues (47,48) demonstrated that activated gd T cells can differentiate and may acquire many features of accessory cells, including increased endocytic activity, which would be required to accumulate zoledronate and to produce IPP.…”

“…Monocytes were suggested to be responsible for gd T cell activation induced by zoledronate through accumulation of IPP and its isomer dimethylallyl pyrophosphate (20). In the study by Roelofs et al (20), quantitative mass spectrometry was used to demonstrate that only monocytes produce substantial amounts of IPP in response to shortterm treatment with zoledronate (2 h), and this was attributed to the higher endocytic capacity of monocytes compared with lymphocytes. Thus, zoledronate rapidly accumulates in monocytes.…”

“…The Ag-presenting element awaits identification, and accessory cell requirements of gd T cell activation are still poorly defined (19). Although monocytes were postulated to be required as a source of IPP in zoledronate-induced gd T cell responses (20), primary human MHC class II + cells were recently reported to be indispensable for gd T cell expansion in response to stimulation with phosphoantigens (21).…”

Cellular Interactions of Synovial Fluid γδ T Cells in Juvenile Idiopathic Arthritis

“…Monocytes and dendritic cells are known to activate PB Vg9 + T cells when they are induced to express high levels of IPP, for example, by zoledronate, an inhibitor of farnesyl pyrophosphate synthase (17,18). To determine whether other cellular components of the synovium also play a role in activating SF Vg9 + T cells, we focused on the role of Sfib, which are critically dependent upon the mevalonate pathway, suggesting that they may continuously produce the Vg9 + Ag IPP (8).…”