IICB-Translational Research Unit of Excellence, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, Kolkata 700091, India.
Division of Cancer Biology and Inflammatory Disorders, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, Kolkata 700032, India.
J Immunol. 2018 Feb 15;200(4):1255-1260. doi: 10.4049/jimmunol.1701118. Epub 2018 Jan 12.
TCRs recognize peptides on MHC molecules and induce downstream signaling, leading to activation and clonal expansion. In addition to the strength of the interaction of TCRs with peptides on MHC molecules, mechanical forces contribute to optimal T cell activation, as reflected by the superior efficiency of immobilized TCR-cross-linking Abs compared with soluble Abs in TCR triggering, although a dedicated mechanotransduction module is not identified. We found that the professional mechanosensor protein Piezo1 is critically involved in human T cell activation. Although a deficiency in Piezo1 attenuates downstream events on ex vivo TCR triggering, a Piezo1 agonist can obviate the need to immobilize TCR-cross-linking Abs. Piezo1-driven Ca influx, leading to calpain activation and organization of cortical actin scaffold, links this mechanosensor to optimal TCR signaling. Thus, we discovered a hitherto unknown regulatory mechanism for human T cell activation and provide the first evidence, to our knowledge, for the involvement of Piezo1 mechanosensors in immune regulation.
TCR 识别 MHC 分子上的肽，并诱导下游信号转导，导致激活和克隆扩增。除了 TCR 与 MHC 分子上的肽相互作用的强度外，机械力有助于最佳的 T 细胞激活，这反映在固定化 TCR 交联 Abs 比可溶性 Abs 在 TCR 触发中更有效，尽管没有确定专门的机械转导模块。我们发现专业的机械传感器蛋白 Piezo1 严重参与人类 T 细胞激活。尽管 Piezo1 缺陷会减弱体外 TCR 触发的下游事件，但 Piezo1 激动剂可以避免固定化 TCR 交联 Abs 的需要。Piezo1 驱动的 Ca2+内流导致钙蛋白酶激活和皮质肌动蛋白支架的组织，将这个机械传感器与最佳的 TCR 信号转导联系起来。因此，我们发现了人类 T 细胞激活的一个迄今未知的调节机制，并提供了我们所知的 Piezo1 机械传感器参与免疫调节的第一个证据。
