Dipartimento di Biotecnologie Molecolari e Scienze della Salute, Università degli Studi di Torino, Via Nizza 52, Torino 10126, Italy.
Centro di Ricerca in Medicina Sperimentale (CeRMS), AOU Città della Salute e della Scienza di Torino, Via Santena 5, Torino 10126, Italy.
Nat Commun. 2017 Jun 5;8:15663. doi: 10.1038/ncomms15663.
Vγ9Vδ2 T cells are activated by phosphoantigens, such as isopentenyl pyrophosphate (IPP), which is generated in the mevalonate pathway of antigen-presenting cells. IPP is released in the extracellular microenvironment via unknown mechanisms. Here we show that the ATP-binding cassette transporter A1 (ABCA1) mediates extracellular IPP release from dendritic cells (DC) in cooperation with apolipoprotein A-I (apoA-I) and butyrophilin-3A1. IPP concentrations in the supernatants are sufficient to induce Vγ9Vδ2 T cell proliferation after DC mevalonate pathway inhibition with zoledronic acid (ZA). ZA treatment increases ABCA1 and apoA-I expression via IPP-dependent LXRα nuclear translocation and PI3K/Akt/mTOR pathway inhibition. These results close the mechanistic gap in our understanding of extracellular IPP release from DC and provide a framework to fine-tune Vγ9Vδ2 T cell activation via mevalonate and PI3K/Akt/mTOR pathway modulation.
γ9δ2 T 细胞被磷酸抗原激活，如异戊烯焦磷酸（IPP），其在抗原呈递细胞的甲羟戊酸途径中产生。IPP 通过未知机制释放到细胞外微环境中。在这里，我们表明 ABCA1 介导树突状细胞（DC）细胞外 IPP 的释放，与载脂蛋白 A-I（apoA-I）和 BTN3A1 合作。在 DC 甲羟戊酸途径被唑来膦酸（ZA）抑制后，上清液中的 IPP 浓度足以诱导 γ9δ2 T 细胞增殖。ZA 通过 IPP 依赖性 LXRα核易位和 PI3K/Akt/mTOR 通路抑制增加 ABCA1 和 apoA-I 的表达。这些结果填补了我们对 DC 细胞外 IPP 释放的机制理解中的空白，并为通过甲羟戊酸和 PI3K/Akt/mTOR 通路调节精细调节 γ9δ2 T 细胞激活提供了一个框架。
