Alkylamines cause Vγ9Vδ2 T-cell activation and proliferation by inhibiting the mevalonate pathway
Alkylamines cause Vγ9Vδ2 T-cell activation and proliferation by inhibiting the mevalonate pathway
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DOI：
10.1182/blood-2005-03-1025
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发表时间：
2006-01-15
期刊：
影响因子：
20.3
通讯作者：
Rogers, MJ
中科院分区：
文献类型：
--
作者：
Thompson, K;Rojas-Navea, J;Rogers, MJ
三类小非肽“抗原”可激活 V gamma 9V delta 2 T 细胞：焦磷酸单酯，例如异戊烯基二磷酸 (IPP)、含氮二磷酸酯 (N-BP) 和烷基胺。然而，我们最近发现，N-BPs 由于抑制法呢基二磷酸合酶（甲羟戊酸途径的关键酶）和 IPR 的细胞内积累而间接激活 V γ 9V δ 2 T 细胞。我们现在表明，烷基胺通过相同的机制激活 V γ 9V δ 2 T 细胞。烷基胺被发现是法呢基二磷酸合酶的弱抑制剂，并导致外周血单核细胞和巨噬细胞中未异戊二烯化的 Rap1A 积累，表明甲羟戊酸途径受到抑制。此外，与 N-BP 一样，烷基胺对 V gamma 9V delta 2 T 细胞的刺激作用通过同时用美伐他汀治疗而被消除。这些发现表明，只有焦磷酸单酯（例如IPP）才是真正的Vγ9Vδ2T细胞激动剂，而烷基胺和N-BP通过涉及IPP积累的常见机制间接激活Vγ9Vδ2T细胞。
Three general classes of small, nonpeptide "antigens" activate V gamma 9V delta 2 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 gamma 9V delta 2 T cells as a consequence of inhibition of farnesyl diphosphate synthase (a key enzyme of the mevalonate pathway) and the intracellular accumulation of IPR We now show that alkylamines activate V gamma 9V delta 2 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 gamma 9V delta 2 T cells was abrogated by simultaneous treatment with mevastatin. These findings suggest that only pyrophosphomonoesters such as IPP are true V gamma 9V delta 2 T-cell agonists, whereas alkylamines and N-BPs indirectly activate V gamma 9V delta 2 T cells through a common mechanism involving the accumulation of IPP.