A cell topography-based mechanism for ligand discrimination by the T cell receptor
A cell topography-based mechanism for ligand discrimination by the T cell receptor
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DOI：
10.1073/pnas.1817255116
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发表时间：
2019-07-09
影响因子：
11.1
通讯作者：
Klenerman, David
中科院分区：
文献类型：
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作者：
Fernandes, Ricardo A.;Ganzinger, Kristina A.;Klenerman, David
T细胞受体（TCR）启动T细胞对病原体和肿瘤的清除。为了避免对宿主的损伤，受体必须能够区分宿主细胞呈现的野生型和突变的自身和非自身肽配体。TCR究竟是如何做到这一点的还不得而知。在静止的T细胞中，由于磷酸酶比细胞表面表达的激酶占优势，TCR在很大程度上未被磷酸化。然而，当激动剂肽通过抗原呈递细胞（APCs）表达的主要组织相容性复合体蛋白呈递给TCR时，会发生非常快速的受体触发，即TCR磷酸化。最近的研究表明，这取决于T细胞与apc接触区域的磷酸酶的局部排除。在这里，我们开发并测试了一种受体触发的定量处理，仅依赖于磷酸酶耗尽的细胞接触中受细胞地形限制的TCR停留时间。利用该模型和实验导出的参数，我们发现配体识别可能主要取决于个体接触的半径接近200nm，与T细胞用来询问其目标的表面突起的尺寸相匹配。该模型不仅正确预测了已知激动剂和非激动剂的相对信号传导能力，而且在没有动力学校对的情况下也实现了这一点。我们的工作提供了一个简单的、定量的、预测性的分子框架来理解为什么TCR触发是如此的选择性和快速，并揭示了，对于一些受体，细胞地形可能影响信号传导结果。
The T cell receptor (TCR) initiates the elimination of pathogens and tumors by T cells. To avoid damage to the host, the receptor must be capable of discriminating between wild-type and mutated self and nonself peptide ligands presented by host cells. Exactly how the TCR does this is unknown. In resting T cells, the TCR is largely unphosphorylated due to the dominance of phosphatases over the kinases expressed at the cell surface. However, when agonist peptides are presented to the TCR by major histocompatibility complex proteins expressed by antigen-presenting cells (APCs), very fast receptor triggering, i.e., TCR phosphorylation, occurs. Recent work suggests that this depends on the local exclusion of the phosphatases from regions of contact of the T cells with the APCs. Here, we developed and tested a quantitative treatment of receptor triggering reliant only on TCR dwell time in phosphatase-depleted cell contacts constrained in area by cell topography. Using the model and experimentally derived parameters, we found that ligand discrimination likely depends crucially on individual contacts being similar to 200 nm in radius, matching the dimensions of the surface protrusions used by T cells to interrogate their targets. The model not only correctly predicted the relative signaling potencies of known agonists and nonagonists but also achieved this in the absence of kinetic proofreading. Our work provides a simple, quantitative, and predictive molecular framework for understanding why TCR triggering is so selective and fast and reveals that, for some receptors, cell topography likely influences signaling outcomes.