通过抗原介导的抗体干扰塑造多克隆反应。

Shaping Polyclonal Responses via Antigen-Mediated Antibody Interference.

作者信息

Yan Le, Wang Shenshen

机构信息

Chan Zuckerberg Biohub, 499 Illinois Street, San Francisco, CA 94158, USA.

Department of Physics and Astronomy, University of California, Los Angeles, Los Angeles, CA 90095, USA.

出版信息

iScience. 2020 Sep 17;23(10):101568. doi: 10.1016/j.isci.2020.101568. eCollection 2020 Oct 23.

DOI:10.1016/j.isci.2020.101568

PMID:33083735

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7530306/

Abstract

Broadly neutralizing antibodies (bnAbs) recognize conserved features of rapidly mutating pathogens and confer universal protection, but they emerge rarely in natural infection. Increasing evidence indicates that seemingly passive antibodies may interfere with natural selection of B cells. Yet, how such interference modulates polyclonal responses is unknown. Here we provide a framework for understanding the role of antibody interference-mediated by multi-epitope antigens-in shaping B cell clonal makeup and the fate of bnAb lineages. We find that, under heterogeneous interference, clones with different intrinsic fitness can collectively persist. Furthermore, antagonism among fit clones (specific for variable epitopes) promotes expansion of unfit clones (targeting conserved epitopes), at the cost of repertoire potency. This trade-off, however, can be alleviated by synergy toward the unfit. Our results provide a physical basis for antigen-mediated clonal interactions, stress system-level impacts of molecular synergy and antagonism, and offer principles to amplify naturally rare clones.

摘要

广泛中和抗体（bnAbs）能够识别快速变异病原体的保守特征并提供普遍保护，但它们在自然感染中很少出现。越来越多的证据表明，看似被动的抗体可能会干扰B细胞的自然选择。然而，这种干扰如何调节多克隆反应尚不清楚。在这里，我们提供了一个框架，用于理解由多表位抗原介导的抗体干扰在塑造B细胞克隆组成和bnAb谱系命运中的作用。我们发现，在异质性干扰下，具有不同内在适应性的克隆可以共同持续存在。此外，适应性强的克隆（针对可变表位）之间的拮抗作用会促进适应性弱的克隆（靶向保守表位）的扩增，代价是库的效力。然而，这种权衡可以通过对适应性弱的克隆的协同作用来缓解。我们的结果为抗原介导的克隆相互作用提供了物理基础，强调了分子协同和拮抗作用对系统水平的影响，并提供了扩增自然罕见克隆的原则。