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.

广泛中和的抗体（bnAbs）可以识别迅速突变的病原体的保守特征并提供普遍保护，但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，用于理解抗体干扰（由多表位抗原介导）在塑造B细胞克隆构成和bnAb谱系的命运中的作用。我们发现，在异构干扰下，具有不同固有适应性的克隆可以共同存在。此外，适合克隆（对可变表位特异）之间的拮抗作用会促进不适合克隆（靶向保守的表位）的扩增，但会降低全部库的效力。但是，这种权衡 可以通过对不合身的协同作用来缓解。我们的结果为抗原介导的克隆相互作用，分子协同作用和拮抗作用在应激系统水平的影响提供了物理基础，并提供了扩增天然稀有克隆的原理。