Alkylamines cause Vγ9Vδ2 T-cell activation and proliferation by inhibiting the mevalonate pathway

Abstract

Three general classes of small, nonpeptide “antigens” activate Vγ9Vδ2 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 Vγ9Vδ2 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 Vγ9Vδ2 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 Vγ9Vδ2T cells was abrogated by simultaneous treatment with mevastatin. These findings suggest that only pyrophosphomonoesters such as IPP are true Vγ9Vδ2 T-cell agonists, whereas alkylamines and N-BPs indirectly activate Vγ9Vδ2 T cells through a common mechanism involving the accumulation of IPP.