The role of the nucleotide-gated cation channels P2X7 and TRPM2 for TCR signalling

P2X7 和 TRPM2 是 T 淋巴细胞表达的阳离子通道，分别由细胞外和细胞内腺嘌呤核苷酸门控。尽管越来越多的证据表明这两个通道在炎症中发挥着关键作用，但它们对 T 细胞的影响仍不清楚。因此，当前项目的主要目标是表征 P2X7 和 TRPM2 在 T 细胞激活早期事件中的作用。为此，我们将使用活细胞 Ca2 和 ATP 成像、HPLC 和膜片钳技术来研究这些通道在 TCR 信号传导中的作用。特别是，我们将检验以下假设：2-脱氧-腺苷二磷酸核糖 (2-deoxy-ADPR)，而不是 ADPR，是 TRPM2 的主要内源激活配体。此外，我们将描述 TCR 和 P2X7 诱导的 ATP 释放、其与免疫突触相关的定位及其与 T 细胞激活的相关性，从而提供细胞内和细胞外核苷酸信号传导世界之间的联系。 P2X7 和 TRPM2 在 TCR 信号传导中的作用特征将为评估针对这两种离子通道的新治疗策略的潜力提供基础。

P2X7 and TRPM2 are cation channels expressed by T lymphocytes that are gated by extra- and intracellular adenine nucleotides, respectively. Although increasing evidence points to a pivotal role of both channels in inflammation, their effects on T cells remain unclear. The primary goal of the current project is thus to characterize the roles of P2X7 and TRPM2 during the early events of T cell activation. To this end, we will use live cell Ca2+ and ATP imaging, HPLC, and patch-clamp techniques to study the roles of these channels in TCR signaling. Especially, we will test the hypothesis that 2-deoxy-adenosine diphosphoribose (2-deoxy-ADPR), instead of ADPR, is the major endogenous activating ligand of TRPM2. Further, we will characterize TCR- and P2X7-induced release of ATP, its localization in relation to the immunological synapse, and its relevance for T-cell activation, thereby providing a link between the worlds of signaling by intra- and extracellular nucleotides. Characterization of the roles of P2X7 and TRPM2 in TCR signaling will provide the basis for assessing the potential of new therapeutic strategies aimed at targeting these two ion channels.