Adaptive mechanical proofreading: a pathway to enhanced humoral immunity

B cells in the germinal center undergo rapid Darwinian-like evolution to produce high-affinity antibodies. Experiments reveal that B cells' ability to extract antigens is vital for their survival, with higher affinity B cells ideally extracting more antigens and being more likely to be selected. Mechanical force exerted by B cells has been found to regulate antigen acquisition, thereby modulating affinity discrimination. However, what forcing characteristics govern functional outcomes is unknown. To uncover the governing principles, we devise two force schemes that differ in their ability to adapt to the system state, that is, whether the process of mechanical proofreading is inert or adaptive. Combining analytics and computer simulations, we discover scaling relationships that help distinguish these schemes in experiment, identify affinity-dependent trade-offs between extraction speed and selection fidelity, and show that, when force can sense and adapt, a negative feedback mechanism originates. This feedback not only decouples B-cell quality from ligand quantity, but also makes extraction efficiency sensitive to spatial arrangement of multiple antigen types, thus having implications for multivalent vaccine design. Altogether, we propose adaptive mechanical proofreading as a paradigm for enhancing humoral immunity via mechanical feedback.