The αβ T Cell Receptor Is an Anisotropic Mechanosensor
The αβ T Cell Receptor Is an Anisotropic Mechanosensor
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DOI：
10.1074/jbc.m109.052712
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发表时间：
2009-11-06
影响因子：
4.8
通讯作者：
Reinherz, Ellis L.
中科院分区：
文献类型：
--
作者：
Kim, Sun Taek;Takeuchi, Koh;Reinherz, Ellis L.
胸腺来源的淋巴细胞通过免疫监视，清除患病细胞，保护哺乳动物宿主免受病毒或癌症相关细胞的改变。在这个过程中，T细胞受体(TCR)通过其二聚体α-β、CD3-β、CD3-β和CD3-Zeta亚基，以未知的结构机制介导T细胞的识别和激活。在这里，抗CD3单抗的位点特异性结合拓扑结构和TCR四次动态变化提供了关键线索。激动剂mAbs足迹到CD3 epsilon叶远端的膜，它们对角接近那里，毗邻促进抗原(PMHC)触发的激活的杠杆状CβFG环。相反，非激动剂单抗以垂直方式结合到CD3 epsilon和CD3 Gamma之间的裂隙上，并且仅在通过光钳施加的外切向力而不是法向力(类似于50皮牛顿)后才起刺激作用。特定的pMHC但不是无关的pMHC在施加类似的力时激活T细胞。这些发现表明，TCR是一个各向异性的机械传感器，在免疫监测过程中，当特定的pMHC连接时，TCR将机械能转化为生化信号。激活抗CD3单抗通过其固有的结合模式模拟这种作用力。考虑到大量的TCR及其特定的pMHC配体，常见的TCR四元变化而不是构象变化可以更好地促进结构信号的启动。
Thymus-derived lymphocytes protect mammalian hosts against virus- or cancer-related cellular alterations through immune surveillance, eliminating diseased cells. In this process, T cell receptors (TCRs) mediate both recognition and T cell activation via their dimeric alpha beta, CD3 epsilon gamma, CD3 epsilon delta, and CD3 zeta zeta subunits using an unknown structural mechanism. Here, site-specific binding topology of anti-CD3 monoclonal antibodies (mAbs) and dynamic TCR quaternary change provide key clues. Agonist mAbs footprint to the membrane distal CD3 epsilon lobe that they approach diagonally, adjacent to the lever-like C beta FG loop that facilitates antigen (pMHC)-triggered activation. In contrast, a non-agonist mAb binds to the cleft between CD3 epsilon and CD3 gamma in a perpendicular mode and is stimulatory only subsequent to an external tangential but not a normal force (similar to 50 piconewtons) applied via optical tweezers. Specific pMHC but not irrelevant pMHC activates a T cell upon application of a similar force. These findings suggest that the TCR is an anisotropic mechanosensor, converting mechanical energy into a biochemical signal upon specific pMHC ligation during immune surveillance. Activating anti-CD3 mAbs mimic this force via their intrinsic binding mode. A common TCR quaternary change rather than conformational alterations can better facilitate structural signal initiation, given the vast array of TCRs and their specific pMHC ligands.