B细胞对膜抗原亲和力的鉴别需要动态校正优于连续触发
Discrimination of Membrane Antigen Affinity by B cells Requires Dominance of Kinetic Proofreading over Serial Triggering
摘要：
B细胞受体（BCR）信号响应膜结合抗原增加与抗原亲和力，一个过程称为亲和力歧视。我们使用计算模型表明，B细胞亲和力歧视需要动力学校对占主导地位的串行接合。我们发现，如果BCR分子在结合抗原后立即变得具有信号传导能力，则随着亲和力增加，串联接合的丧失导致亲和力增加的信号传导减弱。在BCR变得具有信号传导能力之前，抗原保持与BCR结合数秒的阈值时间（类似于动力学校正）是克服由于增加抗原亲和力而导致的串联接合损失所需的，并复制B细胞活化实验中观察到的具有亲和力的B细胞信号转导的单调增加。这一发现与实验观察到的BCR信号传导结构域经历导致Src家族激酶募集的抗原和脂筏介导的构象变化所需的时间（约20秒）非常匹配。我们推测抗原结合阈值时间的物理基础可能在于BCR二聚体的形成时间尺度。后者随着亲和力的增加而降低，导致随着亲和力的增加，阈值抗原结合时间更短。这种依赖于亲和力的动力学校正要求导致与在生物学实验中观察到的非常相似的亲和力辨别。B细胞亲和力的歧视是至关重要的亲和力成熟的过程和高亲和力抗体的生产，因此我们的研究结果在这里有重要的应用，如疫苗设计的影响。
英文摘要：
B cells receptor (BCR) signaling in response to membrane-bound antigen increases with antigen affinity, a process known as affinity discrimination. We use computational modeling to show that B cell affinity discrimination requires that kinetic proofreading predominate over serial engagement. We find that if BCR molecules become signaling-capable immediately upon binding antigen, the loss in serial engagement as affinity increases results in weaker signaling with increasing affinity. A threshold time for antigen to stay bound to BCR for several seconds before the latter becomes signaling-capable, similar to kinetic proofreading, is needed to overcome the loss in serial engagement due to increasing antigen affinity, and replicate the monotonic increase in B cell signaling with affinity observed in B cell activation experiments. This finding matches well 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 Src-family kinase recruitment. We hypothesize that the physical basis of the threshold time of antigen binding may lie in the formation timescale of BCR dimers. The latter decreases with increasing affinity, resulting in shorter threshold antigen binding times as affinity increases. Such an affinity-dependent kinetic proofreading requirement results in affinity discrimination very similar to that observed in biological experiments. B cell affinity discrimination is critical to the process of affinity maturation and the production of high affinity antibodies, and thus our results here have important implications in applications such as vaccine design.
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