Kinetics and Mechanics of Two-Dimensional Interactions between T Cell Receptors and Different Activating Ligands
Kinetics and Mechanics of Two-Dimensional Interactions between T Cell Receptors and Different Activating Ligands
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DOI：
10.1016/j.bpj.2011.11.4018
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发表时间：
2012-01-18
影响因子：
3.4
通讯作者：
van der Merwell, P. Anton
中科院分区：
文献类型：
--
作者：
Robert, Philippe;Aleksic, Milos;van der Merwell, P. Anton
适应性免疫应答由T细胞抗原受体（TCR）和与抗原呈递细胞表面上的主要组织相容性复合物蛋白（MHC）结合的肽抗原（P）的复合物之间的相互作用驱动。许多实验支持T细胞应答在定量和定性上依赖于所谓的TCR/pMHC结合强度的假设。大多数可用的数据是在溶液中测量的结合参数（三维）和pMHC激活效力之间的相关性，表明完整的淋巴细胞激活需要TCR/pMHC相互作用的最小寿命。然而，最近的报告表明，在溶液中测量的配体-受体对（三维）和使用表面结合的分子（二维）测量的结合特性之间的重要差异。其他报告表明，除了动力学参数外，粘合机械强度可能也很重要。在这里，我们使用了层流室监测在单分子水平的重组人TCR和八个pMHC与可变效力之间的二维相互作用。我们发现：1），二维解离速率与先前用相同分子获得的三维参数相当; 2），在结合速率和pMHC的活化效力之间没有发现显著相关性; 3），键机械强度部分地独立于键寿命;和4），键寿命和键强度的适当组合显示与活化效率的最佳相关性。这些结果表明，当代模型的信号产生的T细胞受体可能的改进。总之，我们报告，为我们所知的第一次，在一个无细胞系统中的8个TCR/pMHC夫妇与单键分辨率的二维结合特性。
Adaptive immune responses are driven by interactions between T cell antigen receptors (TCRs) and complexes of peptide antigens (p) bound to Major Histocompatibility Complex proteins (MHC) on the surface of antigen-presenting cells. Many experiments support the hypothesis that T cell response is quantitatively and qualitatively dependent on the so-called strength of TCR/pMHC association. Most available data are correlations between binding parameters measured in solution (three-dimensional) and pMHC activation potency, suggesting that full lymphocyte activation required a minimal lifetime for TCR/pMHC interaction. However, recent reports suggest important discrepancies between the binding properties of ligand-receptor couples measured in solution (three-dimensional) and those measured using surface-bound molecules (two-dimensional). Other reports suggest that bond mechanical strength may be important in addition to kinetic parameters. Here, we used a laminar flow chamber to monitor at the single molecule level the two-dimensional interaction between a recombinant human TCR and eight pMHCs with variable potency. We found that 1), two-dimensional dissociation rates were comparable to three-dimensional parameters previously obtained with the same molecules; 2), no significant correlation was found between association rates and activating potency of pMHCs; 3), bond mechanical strength was partly independent of bond lifetime; and 4), a suitable combination of bond lifetime and bond strength displayed optimal correlation with activation efficiency. These results suggest possible refinements of contemporary models of signal generation by T cell receptors. In conclusion, we reported, for the first time to our knowledge, the two-dimensional binding properties of eight TCR/pMHC couples in a cell-free system with single bond resolution.