Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK; Cancer Research UK Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0RE, UK.
Immunity. 2018 Sep 18;49(3):427-437.e4. doi: 10.1016/j.immuni.2018.08.017. Epub 2018 Sep 11.
How cytotoxic T lymphocytes (CTLs) sense T cell receptor (TCR) signaling in order to specialize an area of plasma membrane for granule secretion is not understood. Here, we demonstrate that immune synapse formation led to rapid localized changes in the phosphoinositide composition of the plasma membrane, both reducing phosphoinositide-4-phosphate (PI(4)P), PI(4,5)P2, and PI(3,4,5)P3 and increasing diacylglycerol (DAG) and PI(3,4)P2 within the first 2 min of synapse formation. These changes reduced negative charge across the synapse, triggering the release of electrostatically bound PIP5 kinases that are required to replenish PI(4,5)P2. As PI(4,5)P2 decreased, actin was depleted from the membrane, allowing secretion. Forced localization of PIP5Kβ across the synapse prevented actin depletion, blocking both centrosome docking and secretion. Thus, PIP5Ks act as molecular sensors of TCR activation, controlling actin recruitment across the synapse, ensuring exquisite co-ordination between TCR signaling and CTL secretion.
细胞毒性 T 淋巴细胞（CTLs）如何感知 T 细胞受体（TCR）信号，以便专门在质膜的一个区域分泌颗粒尚不清楚。在这里，我们证明免疫突触的形成导致质膜中磷酯酰肌醇（PI）组成的快速局部变化，在突触形成的前 2 分钟内，PI(4)P、PI(4,5)P2 和 PI(3,4,5)P3 减少，而二酰基甘油（DAG）和 PI(3,4)P2 增加。这些变化降低了突触的负电荷，引发静电结合的 PIP5 激酶的释放，这些激酶是补充 PI(4,5)P2 所必需的。随着 PI(4,5)P2 的减少，肌动蛋白从膜中耗尽，允许分泌。PIP5Kβ 在突触上的强制定位阻止了肌动蛋白的耗竭，阻断了中心体对接和分泌。因此，PIP5Ks 作为 TCR 激活的分子传感器，控制肌动蛋白在突触上的募集，确保 TCR 信号和 CTL 分泌之间的精确协调。
