Molecular tug of war reveals adaptive potential of an immune cell repertoire

Abstract

The adaptive immune system constantly remodels its lymphocyte repertoire for better protection against future pathogens. Its ability to improve antigen recognition on the fly relies on somatic mutation and selective expansion of B lymphocytes expressing high-affinity antigen receptors. However, this Darwinian process inside an individual appears ineffective, hitting a modest ceiling of antigen-binding affinity. Experiment began to reveal that evolving B cells physically extract antigens from presenting cells and that the extraction level dictates clonal expansion; this challenges the prevailing assumption that the equilibrium constant of receptor-antigen binding determines selective advantage. We present a theoretical framework to explore whether, and how, such tug-of-war antigen extraction impacts the quality and diversity of an evolved B cell repertoire. We find that the apparent ineffectiveness of clonal selection can be a direct consequence of the non-equilibrium nature of antigen recognition. Our theory predicts that the physical strength of antigen tethering under tugging forces sets the affinity ceiling. Meanwhile, the model showed that, intriguingly, cells can use force variability to diversify binding phenotype without compromising fitness, thus remaining plastic under resource constraint. These results suggest that active probing of receptor quality via a molecular tug of war during antigen recognition limit the potency of response to the current antigen, but confer adaptive benefit for protection against future variants. Importantly, a saddle point in the fitness landscape of B cell-phenotype evolution emerges from the tug-of-war setting, which rationalizes multiple key phenomenology and puts forward a role of active physical dynamics in immune adaptation.