HMBPP Analog Prodrugs Bypass Energy-Dependent Uptake To Promote Efficient BTN3A1-Mediated Malignant Cell Lysis by Vγ9Vδ2 T Lymphocyte Effectors
HMBPP Analog Prodrugs Bypass Energy-Dependent Uptake To Promote Efficient BTN3A1-Mediated Malignant Cell Lysis by Vγ9Vδ2 T Lymphocyte Effectors
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DOI：
10.4049/jimmunol.1501833
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发表时间：
2016-07-15
影响因子：
4.4
通讯作者：
Wiemer, Andrew J.
中科院分区：
文献类型：
--
作者：
Kilcollins, Ashley M.;Li, Jin;Wiemer, Andrew J.
V γ 9V δ 2效应T细胞响应于含磷小分子裂解细胞，为灵长类动物提供了去除感染或恶性细胞的独特途径。然而，触发机制仍然不明确。我们检测了人V γ 9V δ 2效应T细胞对天然存在的（E）-4-羟基-3-甲基-丁-2-烯基二磷酸（HMBPP）或合成的细胞渗透性前药双（新戊酰氧基甲基）（E）-4-羟基-3-甲基-丁-2-烯基膦酸酯的应答介导的裂解。CD 27（+）/CD 45 RA（-）Th 1样效应细胞通过一种机制杀死K562靶细胞，该机制可被化合物或TCR Ab增强，并被Src抑制或亲酪蛋白3同种型A1（BTN 3A 1）破坏阻断。4 ℃预处理降低HMBPP诱导的裂解，但不降低双（新戊酰氧基甲基）（E）-4-羟基-3-甲基-丁-2-烯基膦酸酯诱导的裂解。总之，我们的结果表明，HMBPP内化到靶细胞中是V γ 9V δ 2效应T细胞的BTN 3A 1依赖性裂解所需的。前药类似物的活性增强是由于其能够绕过HMBPP进入所需的途径。这些发现支持由BTN 3A 1的小分子诱导驱动的T细胞触发的由内而外模型。
V gamma 9V delta 2 effector T cells lyse cells in response to phosphorus-containing small molecules, providing primates a unique route to remove infected or malignant cells. Yet, the triggering mechanisms remain ill defined. We examined lysis mediated by human V gamma 9V delta 2 effector T cells in response to the naturally occurring (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) or a synthetic cell-permeable prodrug, bis (pivaloyloxymethyl) (E)-4-hydroxy-3-methyl-but-2-enyl phosphonate. CD27(+)/CD45RA(-) Th1-like effector cells killed K562 target cells through a mechanism that could be enhanced by either compound or TCR Ab and blocked by Src inhibition or butyrophilin 3 isoform A1 (BTN3A1) disruption. Pretreatment at 4 degrees C decreased HMBPP-induced lysis but did not reduce lysis induced by bis (pivaloyloxymethyl) (E)-4-hydroxy-3-methyl-but-2-enyl phosphonate. Together, our results show that internalization of HMBPP into target cells is required for BTN3A1-dependent lysis by V gamma 9V delta 2 effector T cells. The enhanced activity of the prodrug analog is due to its ability to bypass the pathways required for entry of HMBPP. These findings support an inside-out model of T cell triggering driven by small-molecule induction of BTN3A1.