Alkylamines cause Vgamma9Vdelta2 T-cell activation and proliferation by inhibiting the mevalonate pathway

Three general classes of small, nonpeptide "antigens" activate Vgamma9Vdelta2 T cells: pyrophosphomonoesters, such as isopentenyl diphosphate (IPP), nitrogen-containing bisphosphonates (N-BPs), and alkylamines. However, we have shown recently that N-BPs indirectly activate Vgamma9Vdelta2 T cells as a consequence of inhibition of farnesyl diphosphate synthase (a key enzyme of the mevalonate pathway) and the intracellular accumulation of IPP. We now show that alkylamines activate Vgamma9Vdelta2 T cells by the same mechanism. Alkylamines were found to be weak inhibitors of farnesyl diphosphate synthase and caused accumulation of unprenylated Rap1A in peripheral blood mononuclear cells and macrophages, indicative of inhibition of the mevalonate pathway. Furthermore, as with N-BPs, the stimulatory effect of the alkylamines on Vgamma9Vdelta2T cells was abrogated by simultaneous treatment with mevastatin. These findings suggest that only pyrophosphomonoesters such as IPP are true Vgamma9Vdelta2 T-cell agonists, whereas alkylamines and N-BPs indirectly activate Vgamma9Vdelta2 T cells through a common mechanism involving the accumulation of IPP.