Dipartimento di Oncologia, Università degli Studi di Torino, Turin, Italy.
Laboratorio di Immunologia dei Tumori del Sangue (LITS), Centro Interdipartimentale di Ricerca in Biologia Molecolare (CIRBM), Università degli Studi di Torino, Turin, Italy.
Front Immunol. 2018 Jun 8;9:1246. doi: 10.3389/fimmu.2018.01246. eCollection 2018.
Human Vγ9Vδ2 T cells have the capacity to detect supra-physiological concentrations of phosphoantigens (pAgs) generated by the mevalonate (Mev) pathway of mammalian cells under specific circumstances. Isopentenyl pyrophosphate (IPP) is the prototypic pAg recognized by Vγ9Vδ2 T cells. B-cell derived tumor cells (i.e., lymphoma and myeloma cells) and dendritic cells (DCs) are privileged targets of Vγ9Vδ2 T cells because they generate significant amounts of IPP which can be boosted with zoledronic acid (ZA). ZA is the most potent aminobisphosphonate (NBP) clinically available to inhibit osteoclast activation and a very potent inhibitor of farnesyl pyrophosphate synthase in the Mev pathway. ZA-treated DCs generate and release in the supernatants picomolar IPP concentrations which are sufficient to induce the activation of Vγ9Vδ2 T cells. We have recently shown that the ATP-binding cassette transporter A1 (ABCA1) plays a major role in the extracellular release of IPP from ZA-treated DCs. This novel ABCA1 function is fine-tuned by physical interactions with IPP, apolipoprotein A-I (apoA-I), and butyrophilin-3A1 (BTN3A1). The mechanisms by which soluble IPP induces Vγ9Vδ2 T-cell activation remain to be elucidated. It is possible that soluble IPP binds to BTN3A1, apoA-I, or other unknown molecules on the cell surface of bystander cells like monocytes, NK cells, Vγ9Vδ2 T cells, or any other cell locally present. Investigating this scenario may represent a unique opportunity to further characterize the role of BTN3A1 and other molecules in the recognition of soluble IPP by Vγ9Vδ2 T cells.
人 Vγ9Vδ2 T 细胞在特定条件下具有检测哺乳动物细胞甲羟戊酸（Mev）途径产生的超生理浓度磷酸抗原（pAg）的能力。异戊烯焦磷酸（IPP）是被 Vγ9Vδ2 T 细胞识别的典型 pAg。B 细胞来源的肿瘤细胞（即淋巴瘤和骨髓瘤细胞）和树突状细胞（DC）是 Vγ9Vδ2 T 细胞的特权靶标，因为它们产生大量的 IPP，可用唑来膦酸（ZA）来增强。ZA 是临床上最有效的抑制破骨细胞激活的氨基双膦酸盐（NBP），也是 Mev 途径中法呢基焦磷酸合酶的非常有效的抑制剂。ZA 处理的 DC 在细胞外间隙中产生并释放皮摩尔浓度的 IPP，足以诱导 Vγ9Vδ2 T 细胞的激活。我们最近表明，三磷酸腺苷结合盒转运蛋白 A1（ABCA1）在 ZA 处理的 DC 中外排 IPP 中起主要作用。这种新的 ABCA1 功能通过与 IPP、载脂蛋白 A-I（apoA-I）和 BTN3A1 的物理相互作用进行微调。可溶性 IPP 诱导 Vγ9Vδ2 T 细胞活化的机制仍有待阐明。可能的情况是，可溶性 IPP 与 BTN3A1、apoA-I 或其他未知分子结合，这些分子位于旁观者细胞（如单核细胞、NK 细胞、Vγ9Vδ2 T 细胞或任何其他局部存在的细胞）的细胞表面。研究这种情况可能是进一步表征 BTN3A1 和其他分子在 Vγ9Vδ2 T 细胞识别可溶性 IPP 中的作用的独特机会。
