Discrimination of membrane antigen affinity by B cells requires dominance of kinetic proofreading over serial engagement.
Discrimination of membrane antigen affinity by B cells requires dominance of kinetic proofreading over serial engagement.
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B 细胞对膜抗原亲和力的区分需要动力学校对优于串行接合。
DOI：
10.1038/cmi.2011.29
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发表时间：
2012
影响因子：
24.1
通讯作者：
Raychaudhuri,Subhadip
中科院分区：
文献类型：
--
作者：
Tsourkas,PhilipposK;Liu,Wanli;Das,SomkanyaC;Pierce,SusanK;Raychaudhuri,Subhadip
响应于膜结合抗原的B细胞受体信号传导随着抗原亲和力而增加，这一过程称为亲和力辨别。我们使用计算建模表明，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B细胞受体在抗原结合后立即变得具有信号传导能力，这导致随着亲和力增加而减少的连续接合，则亲和力增加可能导致信号传导减弱。相反，抗原必须与B细胞受体结合几秒钟的阈值时间，然后才能发出信号，这一过程类似于动力学校对。该过程克服了由于抗原亲和力增加而导致的串联接合的损失，并且复制了在B细胞活化实验中已经观察到的B细胞信号传导随着亲和力增加而单调增加。这一发现与实验观察到的B细胞受体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（1020 s）非常匹配。我们推测，抗原结合的阈值时间的物理基础可能在于B细胞受体二聚体的形成时间尺度。二聚体形成所需的时间随着抗原亲和力的增加而减少，从而随着亲和力的增加而导致更短的阈值抗原结合时间。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中，高亲和力抗体的生产，因此我们的研究结果有重要的应用，如疫苗设计的影响。
B-cell receptor 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 B-cell receptors become signaling-capable immediately upon antigen binding, which results in decreasing serial engagement as affinity increases, then increasing affinity can lead to weaker signaling. Rather, antigen must stay bound to B-cell receptors for a threshold time of several seconds before becoming signaling-capable, a process similar to kinetic proofreading. This process overcomes the loss in serial engagement due to increasing antigen affinity, and replicates the monotonic increase in B-cell signaling with increasing affinity that has been observed in B-cell activation experiments. This finding matches well with the experimentally observed time (∼ 20 s) required for the B-cell receptor signaling domains to undergo antigen and lipid raft-mediated conformational changes that lead to Src-family kinase recruitment. We hypothesize that the physical basis for a threshold time of antigen binding might lie in the formation timescale of B-cell receptor dimers. The time required for dimer formation decreases with increasing antigen affinity, thereby 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 have important implications in applications such as vaccine design.