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Mapping the stochastic sequence of individual ligand-receptor binding events to cellular activation: T cells act on the rare events
Science Signaling ( IF 6.7 ) Pub Date : 2019-01-15 , DOI: 10.1126/scisignal.aat8715
Jenny J. Y. Lin 1 , Shalini T. Low-Nam 1 , Katherine N. Alfieri 1 , Darren B. McAffee 1 , Nicole C. Fay 1 , Jay T. Groves 1
Affiliation  

T cell receptor (TCR) binding to agonist peptide major histocompatibility complex (pMHC) triggers signaling events that initiate T cell responses. This system is remarkably sensitive, requiring only a few binding events to successfully activate a cellular response. On average, activating pMHC ligands exhibit mean dwell times of at least a few seconds when bound to the TCR. However, a T cell accumulates pMHC-TCR interactions as a stochastic series of discrete, single-molecule binding events whose individual dwell times are broadly distributed. With activation occurring in response to only a handful of such binding events, individual cells are unlikely to experience the average binding time. Here, we mapped the ensemble of pMHC-TCR binding events in space and time while simultaneously monitoring cellular activation. Our findings revealed that T cell activation hinges on rare, long–dwell time binding events that are an order of magnitude longer than the average agonist pMHC-TCR dwell time. Furthermore, we observed that short pMHC-TCR binding events that were spatially correlated and temporally sequential led to cellular activation. These observations indicate that T cell antigen discrimination likely occurs by sensing the tail end of the pMHC-TCR binding dwell time distribution rather than its average properties.



中文翻译:

将单个配体-受体结合事件的随机序列映射到细胞激活:T细胞对罕见事件起作用

与激动剂肽主要组织相容性复合物(pMHC)结合的T细胞受体(TCR)触发启动T细胞反应的信号事件。该系统非常灵敏,仅需几个结合事件即可成功激活细胞应答。平均而言,激活的pMHC配体与TCR结合时,平均停留时间至少为几秒钟。但是,T细胞积累的pMHC-TCR相互作用是一系列离散的,单分子结合事件的随机序列,其单个驻留时间分布广泛。由于仅响应少数此类结合事件而发生激活,因此单个细胞不太可能经历平均结合时间。在这里,我们在空间和时间上绘制了pMHC-TCR结合事件的集合,同时监测了细胞的活化。我们的发现表明,T细胞活化取决于罕见的长停留时间结合事件,该事件比平均激动剂pMHC-TCR停留时间长一个数量级。此外,我们观察到,短的pMHC-TCR结合事件在空间上相关并且在时间上相继导致细胞激活。这些观察结果表明,通过感知pMHC-TCR结合驻留时间分布的尾端而不是其平均特性,可能会发生T细胞抗原区分。

更新日期:2019-01-16
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