Early T cell receptor signals globally modulate ligand:receptor affinities during antigen discrimination.
Early T cell receptor signals globally modulate ligand:receptor affinities during antigen discrimination.
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DOI：
10.1073/pnas.1613140114
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发表时间：
2017-11-14
影响因子：
11.1
通讯作者：
Groves JT
中科院分区：
文献类型：
--
作者：
Pielak RM;O'Donoghue GP;Lin JJ;Alfieri KN;Fay NC;Low-Nam ST;Groves JT
T细胞的抗原识别是基于T细胞受体（TCR）与其肽主要组织相容性复合物（pMHC）配体结合的细微差异。虽然这种结合特征很容易在重构的生化系统中以很高的精度映射，但不太清楚这些相互作用在活细胞环境中如何受到影响。在这里，我们利用单分子成像来单独解析活T细胞中的所有pMHC：TCR结合事件。定量测量揭示了一个积极的反馈机制，全球调制的概率pMHC：TCR结合在整个细胞-细胞界面，而不影响解结合率。其结果是增加了TCR在最初几次分子相遇后扫描抗原pMHC的效率。T细胞的抗原识别发生在T细胞和抗原呈递细胞之间的连接处。众多的粘附，信号传导和共刺激分子之间的Juxtacrine结合定义了这种细胞-细胞界面的地形和横向几何形状，其中T细胞受体（TCR）和肽主要组织相容性复合物（pMHC）相互作用。这些对受体和配体运动的物理限制具有调节其分子结合特性的显著潜力。在这里，我们监测单个配体：受体结合和非结合事件的空间和时间的单分子成像活的原代T细胞的一系列不同的pMHC配体和表面密度。pMHC：TCR和CD 80：CD 28结合事件的直接观察揭示了pMHC和CD 80配体对其各自受体的原位亲和力由细胞经历的激动剂pMHC：TCR相互作用的稳态数量调节。通过解析每一个pMHC：TCR相互作用，很明显，这种协同性是通过增加动力学结合速率而不改变解离速率来实现的，并且具有非空间定位的组分。此外，在T细胞活化概率低的条件下观察到正协同性。这种TCR介导的反馈是对细胞间连接的全局影响。它是由最初几个单独的pMHC：TCR结合事件触发的，并在T细胞致力于活化之前有效地提高TCR扫描抗原的效率。
Antigen discrimination by T cells is based on subtle differences in binding of the T cell receptor (TCR) for its peptide major histocompatibility complex (pMHC) ligand. While such binding characteristics are readily mapped with great precision in reconstituted biochemical systems, it is less clear how these interactions are affected in the live cell environment. Here we utilize single-molecule imaging to individually resolve all of the pMHC:TCR binding events in live T cells. The quantitative measurements reveal an active feedback mechanism that globally modulates the probability of pMHC:TCR binding throughout the cell–cell interface, without affecting the unbinding rate. The result is to increase the efficiency with which TCRs scan for antigen pMHC after the first few molecular encounters have occurred. Antigen discrimination by T cells occurs at the junction between a T cell and an antigen-presenting cell. Juxtacrine binding between numerous adhesion, signaling, and costimulatory molecules defines both the topographical and lateral geometry of this cell–cell interface, within which T cell receptor (TCR) and peptide major histocompatibility complex (pMHC) interact. These physical constraints on receptor and ligand movement have significant potential to modulate their molecular binding properties. Here, we monitor individual ligand:receptor binding and unbinding events in space and time by single-molecule imaging in live primary T cells for a range of different pMHC ligands and surface densities. Direct observations of pMHC:TCR and CD80:CD28 binding events reveal that the in situ affinity of both pMHC and CD80 ligands for their respective receptors is modulated by the steady-state number of agonist pMHC:TCR interactions experienced by the cell. By resolving every single pMHC:TCR interaction it is evident that this cooperativity is accomplished by increasing the kinetic on-rate without altering the off-rate and has a component that is not spatially localized. Furthermore, positive cooperativity is observed under conditions where the T cell activation probability is low. This TCR-mediated feedback is a global effect on the intercellular junction. It is triggered by the first few individual pMHC:TCR binding events and effectively increases the efficiency of TCR scanning for antigen before the T cell is committed to activation.
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T细胞共刺激和共抑制的分子机制。
DOI：
10.1038/nri3405
发表时间：
2013-04
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.8
作者：
Daniels, Mark A.;Teixeiro, Emma;Palmer, Ed
通讯作者：
Palmer, Ed
DOI：
10.1073/pnas.92.11.5042
发表时间：
1995-05-23
影响因子：
11.1
作者：
MCKEITHAN, TW
通讯作者：
MCKEITHAN, TW
DOI：
10.1073/pnas.1305766110
发表时间：
2013-09-17
影响因子：
11.1
作者：
Hu, Jinglei;Lipowsky, Reinhard;Weikl, Thomas R.
通讯作者：
Weikl, Thomas R.
DOI：
10.1073/pnas.0902621106
发表时间：
2009-08-04
影响因子：
11.1
作者：
Hartman, Nina C.;Nye, Jeffrey A.;Groves, Jay T.
通讯作者：
Groves, Jay T.