Alkylamines cause V¿9Vd2 T-cell activation by inhibiting the mevalonate pathway

Three general classes of small, nonpeptide "antigens" activate V¿9Vd2 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 V¿9Vd2 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 V¿9Vd2 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 V¿9Vd2 T cells was abrogated by simultaneous treatment with mevastatin. These findings suggest that only pyrophosphomonoesters such as IPP are true V¿9Vd2 T-cell agonists, whereas alkylamines and N-BPs indirectly activate V¿9Vd2 T cells through a common mechanism involving the accumulation of IPP.