T-dependent B cell responses to Plasmodium induce antibodies that form a high-avidity multivalent complex with the circumsporozoite protein
T-dependent B cell responses to Plasmodium induce antibodies that form a high-avidity multivalent complex with the circumsporozoite protein
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DOI：
10.1371/journal.ppat.1006469
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发表时间：
2017-07-01
期刊：
影响因子：
6.7
通讯作者：
Cockburn, Ian A.
中科院分区：
文献类型：
--
作者：
Fisher, Camilla R.;Sutton, Henry J.;Cockburn, Ian A.
恶性疟原虫环子孢子蛋白（CSP）的重复区是一个主要的疫苗抗原，因为它可以被寄生虫中和抗体靶向，然而，很少有人知道这种相互作用。我们使用等温滴定量热法，X-射线晶体学和诱变验证的建模来分析鼠中和抗体与恶性疟原虫CSP的结合。引人注目的是，我们发现CSP的重复区域被多种抗体结合。这种重复模式允许单个F-AB结构域的多种弱相互作用累积并产生解离常数在低nM范围内的复合物。由于CSP蛋白可以潜在地交联多种B细胞受体（BCR），我们假设B细胞应答可能是T细胞非依赖性的。然而，虽然在缺乏T细胞帮助的小鼠中有适度的反应，但大部分反应是T细胞依赖性的。通过对近交系小鼠CSP重复序列特异性B细胞的BCR进行测序，我们发现这些细胞经历了体细胞超突变和亲和力成熟，表明了T依赖性反应。最后，我们发现响应B细胞的BCR库是有限的，这表明重复序列的结构简单性可能限制了免疫反应的广度。
The repeat region of the Plasmodium falciparum circumsporozoite protein (CSP) is a major vaccine antigen because it can be targeted by parasite neutralizing antibodies; however, little is known about this interaction. We used isothermal titration calorimetry, X-ray crystallography and mutagenesis-validated modeling to analyze the binding of a murine neutralizing antibody to Plasmodium falciparum CSP. Strikingly, we found that the repeat region of CSP is bound by multiple antibodies. This repeating pattern allows multiple weak interactions of single F-AB domains to accumulate and yield a complex with a dissociation constant in the low nM range. Because the CSP protein can potentially cross-link multiple B cell receptors (BCRs) we hypothesized that the B cell response might be T cell independent. However, while there was a modest response in mice deficient in T cell help, the bulk of the response was T cell dependent. By sequencing the BCRs of CSP-repeat specific B cells in inbred mice we found that these cells underwent somatic hypermutation and affinity maturation indicative of a T-dependent response. Last, we found that the BCR repertoire of responding B cells was limited suggesting that the structural simplicity of the repeat may limit the breadth of the immune response.