B细胞对膜抗原的亲和力识别需要动力学校正
Affinity Discrimination in B cells in Response to Membrane Antigen Requires Kinetic Proofreading
摘要：
B细胞对抗原的信号传导与抗原亲和力成比例，这一过程称为亲和力辨别。最近的研究表明，B细胞可以在抗原呈递细胞（APC）表面以膜结合形式获得抗原，在B细胞/APC接触的几秒钟内启动信号传导。在B细胞/APC接触的最早阶段，B细胞表面突起上的B细胞受体（BCR）与APC表面上的抗原结合，并形成10-100个BCR/抗原复合物的微簇。在这项研究中，我们使用计算建模表明，在BCR-抗原微簇水平的B细胞亲和力歧视需要一个阈值抗原结合时间，以类似于动力学校对的方式。我们发现，如果BCR分子在结合抗原后立即具有信号传导能力，则由于koff降低而导致键寿命增加，从而导致串联接合损失。这导致随着亲和力增加，信号强度降低。抗原在BCR变得能够发出信号之前保持与BCR结合的阈值时间有利于高亲和力BCR-抗原键，因为这些长寿命键可以比低亲和力键更好地满足阈值时间要求。约10秒的阈值抗原结合时间导致具有亲和力的信号传导单调增加，复制了在B细胞活化实验中观察到的亲和力辨别模式。该时间与实验观察到的BCR信号传导结构域经历导致与Syk缔合的抗原和脂筏介导的构象变化所需的时间（约20秒）匹配良好（在数量级内）。
英文摘要：
B cells signaling in response to antigen is proportional to antigen affinity, a process known as affinity discrimination. Recent research suggests that B cells can acquire antigen in membrane-bound form on the surface of antigen-presenting cells (APCs), with signaling being initiated within a few seconds of B cell/APC contact. During the earliest stages of B cell/APC contact, B cell receptors (BCRs) on protrusions of the B cell surface bind to antigen on the APC surface and form micro-clusters of 10-100 BCR/Antigen complexes. In this study, we use computational modeling to show that B cell affinity discrimination at the level of BCR-antigen micro-clusters requires a threshold antigen binding time, in a manner similar to kinetic proofreading. We find that if BCR molecules become signaling-capable immediately upon binding antigen, there is a loss in serial engagement due to the increase in bond lifetime as koff decreases. This results in decreasing signaling strength as affinity increases. A threshold time for antigen to stay bound to BCR before the latter becomes signaling-capable favors high affinity BCR-antigen bonds, as these long-lived bonds can better fulfill the threshold time requirement than low-affinity bonds. A threshold antigen binding time of ~10 seconds results in monotonically increasing signaling with affinity, replicating the affinity discrimination pattern observed in B cell activation experiments. This time matches well (within order of magnitude) with the experimentally observed time (~ 20 seconds) required for the BCR signaling domains to undergo antigen and lipid raft-mediated conformational changes that lead to association with Syk.
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