How Germinal Centers Evolve Broadly Neutralizing Antibodies: the Breadth of the Follicular Helper T Cell Response
How Germinal Centers Evolve Broadly Neutralizing Antibodies: the Breadth of the Follicular Helper T Cell Response
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DOI：
10.1128/jvi.00983-17
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发表时间：
2017-11-01
影响因子：
5.4
通讯作者：
Perelson, Alan S.
中科院分区：
文献类型：
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作者：
de Boer, Rob J.;Perelson, Alan S.
许多HIV-1感染患者进化出广泛中和抗体（bnAb）。这种进化过程通常需要几年时间，并且由于选择发生在基于抗体亲和力的生殖中心，因此人们对其了解甚少。具有最高亲和力受体的B细胞倾向于从滤泡树突细胞（FDC）网络获得最多抗原，并将最高密度的同源肽呈递给滤泡辅助T（Tfh）细胞，其向B细胞提供存活信号。因此，预期bnAb仅在B细胞谱系进化宽度一致地捕获并呈递比其它谱系的更特异性B细胞更多的肽至Tfh细胞时进化。在这里，我们开发的数学模型，Tfh细胞在germination中心明确定义在这个复杂的进化过程中的选择机制。我们的研究结果表明，广泛反应的B细胞呈现高密度的肽结合主要组织相容性复合体II类分子（pMHC）很容易被B细胞竞争，响应HIV-1的谱系，暂时占主导地位的宿主病毒种群。相反，如果广泛反应的B细胞从FDC网络获得多种HIV-1蛋白，并呈现多种pMHC的高度多样性，则它们可以被生发中心的大部分Tfh细胞库拯救。在这种情况下，bnAb的进化更加一致。增加Tfh细胞应答的幅度或Tfh细胞库的宽度显著促进bnAb的进化。由于接种几种HIV-1蛋白可以增加感染的强度和广度，因此需要进行实验测试。重要信息许多HIV感染患者会慢慢进化出抗体，这些抗体可以中和多种病毒。这种广泛中和抗体（bnAb）将来可能成为治疗剂。bnAb出现得很晚，患者通常不受其保护。目前，我们还不明白为什么这需要这么长时间，以及免疫系统如何选择广泛的中和能力。通常，基于亲和力而不是宽度来选择抗体。我们开发了数学模型来研究免疫系统可以选择广泛中和能力的两种不同机制。其中之一是基于不同的滤泡辅助T（Tfh）细胞在生发中心的剧目。我们认为，广泛反应的B细胞可能与更大比例的这一库相互作用，并证明这将选择bnAb。有趣的是，这表明通过疫苗接种扩大Tfh细胞库可以加速bnAb的进化。
Many HIV-1-infected patients evolve broadly neutralizing antibodies (bnAbs). This evolutionary process typically takes several years and is poorly understood as selection taking place in germinal centers occurs on the basis of antibody affinity. B cells with the highest-affinity receptors tend to acquire the most antigen from the follicular dendritic cell (FDC) network and present the highest density of cognate peptides to follicular helper T (Tfh) cells, which provide survival signals to the B cell. bnAbs are therefore expected to evolve only when the B cell lineage evolving breadth is consistently capturing and presenting more peptides to Tfh cells than other lineages of more specific B cells. Here we develop mathematical models of Tfh cells in germinal centers to explicitly define the mechanisms of selection in this complex evolutionary process. Our results suggest that broadly reactive B cells presenting a high density of peptides bound to major histocompatibility complex class II molecules (pMHC) are readily outcompeted by B cells responding to lineages of HIV-1 that transiently dominate the within host viral population. Conversely, if broadly reactive B cells acquire a large variety of several HIV-1 proteins from the FDC network and present a high diversity of several pMHC, they can be rescued by a large fraction of the Tfh cell repertoire in the germinal center. Under such circumstances the evolution of bnAbs is much more consistent. Increasing either the magnitude of the Tfh cell response or the breadth of the Tfh cell repertoire markedly facilitates the evolution of bnAbs. Because both the magnitude and breadth can be increased by vaccination with several HIV-1 proteins, this calls for experimental testing.IMPORTANCE Many HIV-infected patients slowly evolve antibodies that can neutralize a large variety of viruses. Such broadly neutralizing antibodies (bnAbs) could in the future become therapeutic agents. bnAbs appear very late, and patients are typically not protected by them. At the moment, we fail to understand why this takes so long and how the immune system selects for broadly neutralizing capacity. Typically, antibodies are selected based on affinity and not on breadth. We developed mathematical models to study two different mechanisms by which the immune system can select for broadly neutralizing capacity. One of these is based upon the repertoire of different follicular helper T (Tfh) cells in germinal centers. We suggest that broadly reactive B cells may interact with a larger fraction of this repertoire and demonstrate that this would select for bnAbs. Intriguingly, this suggests that broadening the Tfh cell repertoire by vaccination may speed up the evolution of bnAbs.