Synthesis of a Phosphoantigen Prodrug that Potently Activates Vγ9Vδ2 T-Lymphocytes
Synthesis of a Phosphoantigen Prodrug that Potently Activates Vγ9Vδ2 T-Lymphocytes
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DOI：
10.1016/j.chembiol.2014.06.006
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发表时间：
2014-08-14
影响因子：
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通讯作者：
Wiemer, Andrew J.
中科院分区：
文献类型：
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作者：
Hsiao, Chia-Hung Christine;Lin, Xiaochen;Wiemer, Andrew J.
磷酸化抗原敏感的V γ 9V δ 2 T细胞是感染和恶性肿瘤的重要应答者。然而，磷抗原刺激V γ 9V δ 2 T细胞的机制尚不清楚。在这里，我们合成了磷酸化抗原前药，并使用它们来证明磷酸化抗原的细胞内递送是其活性所必需的。新戊酰氧基甲基前药是迄今为止描述的最有效的磷酸化抗原，相对于先前最有效的化合物（E）-4-羟基-3-甲基-丁-2-烯基焦磷酸（HMBPP），其对来自人外周血的V γ 9V δ 2 T细胞具有更强的刺激，并且诱导Daudi淋巴瘤细胞裂解的能力更强。我们证明了磷酸化抗原和嗜丁酸蛋白3A 1（BTN 3A 1）的细胞内区域之间的高结合亲和力，定位于PRY/SPRY（B30.2）结构域，但也影响膜近端区域。我们的研究结果促进了癌症免疫治疗的磷酸化抗原前药方法，并揭示了V γ 9V δ 2 T细胞活化机制的基本方面。
Phosphoantigen-sensitive V gamma 9V delta 2 T cells are important responders to infections and malignancy. However, the mechanisms by which phosphoantigens stimulate V gamma 9V delta 2 T cells are unclear. Here, we synthesized phosphoantigen prodrugs and used them to demonstrate that intracellular delivery of phosphoantigens is required for their activity. The pivaloyloxymethyl prodrug is the most potent phosphoantigen described to date, with stronger stimulation of V gamma 9V delta 2 T cells from human peripheral blood and greater ability to induce lysis of Daudi lymphoma cells relative to the previously most potent compound, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP). We demonstrate high binding affinity between phosphoantigens and the intracellular region of butyrophilin 3A1 (BTN3A1), localized to the PRY/SPRY (B30.2) domain, but also affecting the membrane proximal region. Our findings promote a phosphoantigen prodrug approach for cancer immunotherapy and unravel fundamental aspects of the mechanisms of V gamma 9V delta 2 T cell activation.