DNA-based nanoparticle tension sensors reveal that T-cell receptors transmit defined pN forces to their antigens for enhanced fidelity
DNA-based nanoparticle tension sensors reveal that T-cell receptors transmit defined pN forces to their antigens for enhanced fidelity
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DOI：
10.1073/pnas.1600163113
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发表时间：
2016-05-17
影响因子：
11.1
通讯作者：
Salaita, Khalid
中科院分区：
文献类型：
--
作者：
Liu, Yang;Blanchfield, Lori;Salaita, Khalid
当T细胞受体（TCR）在抗原呈递细胞（APC）表面遇到其抗原配体肽-主要组织相容性复合物（pMHC）时，T细胞被触发。由于T细胞是高度迁移的，并且抗原识别发生在T细胞物理接触APC的膜间连接处，因此T细胞是否将确定的力传递到其TCR复合物以及化学机械偶联是否影响免疫功能是长期存在的问题。在这里，我们开发了基于DNA的金纳米颗粒张力传感器，以提供，据我们所知，在T细胞活化过程中的单个TCR-pMHC复合物的第一个pN张力图。我们发现，幼稚T细胞利用细胞骨架偶联在配体结合和初始钙信号传导之前的几秒钟内将12-19 pN的力传递到它们的TCR。CD 8辅助受体结合和淋巴细胞特异性激酶信号传导是抗原介导的细胞扩散和力产生所必需的。淋巴细胞功能相关抗原1（LFA-1）介导的粘附通过将其强度增强至>19 pN的值来调节TCR-pMHC张力，并在空间上将TCR力的位置重新组织到位于迁移T细胞后缘的区域，从而证明了TCR和LFA-1受体信号传导之间的化学机械串扰。最后，当使用机械不稳定的DNA系链将TCR力化学消除或物理“过滤”至低于类似于12 pN的水平时，T细胞显示出对抗原激动剂的减弱的和较差的特异性应答。因此，我们得出结论，T细胞用pN分辨率调节TCR机制，以产生特异性免疫应答所必需的激动剂质量的检查点。
T cells are triggered when the T-cell receptor (TCR) encounters its antigenic ligand, the peptide-major histocompatibility complex (pMHC), on the surface of antigen presenting cells (APCs). Because T cells are highly migratory and antigen recognition occurs at an intermembrane junction where the T cell physically contacts the APC, there are long-standing questions of whether T cells transmit defined forces to their TCR complex and whether chemomechanical coupling influences immune function. Here we develop DNA-based gold nanoparticle tension sensors to provide, to our knowledge, the first pN tension maps of individual TCR-pMHC complexes during T-cell activation. We show that naive T cells harness cytoskeletal coupling to transmit 12-19 pN of force to their TCRs within seconds of ligand binding and preceding initial calcium signaling. CD8 coreceptor binding and lymphocyte-specific kinase signaling are required for antigen-mediated cell spreading and force generation. Lymphocyte functionassociated antigen 1 (LFA-1) mediated adhesion modulates TCR-pMHC tension by intensifying its magnitude to values >19 pN and spatially reorganizes the location of TCR forces to the kinapse, the zone located at the trailing edge of migrating T cells, thus demonstrating chemomechanical crosstalk between TCR and LFA-1 receptor signaling. Finally, T cells display a dampened and poorly specific response to antigen agonists when TCR forces are chemically abolished or physically "filtered" to a level below similar to 12 pN using mechanically labile DNA tethers. Therefore, we conclude that T cells tune TCR mechanics with pN resolution to create a checkpoint of agonist quality necessary for specific immune response.