Molecular Tug of War Reveals Adaptive Potential of an Immune Cell Repertoire

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 somatic mutation and selective expansion of B lymphocytes expressing high-affinity receptors. However, this rapid evolution inside an individual appears ineffective, hitting a modest ceiling antigen-binding affinity. Only recently, experiments began reveal that evolving cells physically extract antigens from presenting using active forces, extraction level dictates clonal fitness. These observations challenge prevailing view equilibrium constant receptor-antigen binding determines advantage cell clone. Here, we present theoretical framework explore ways in which tug-of-war impacts quality diversity evolved repertoire. We propose apparent “ineffectiveness” vivo selection can be direct consequence nonequilibrium recognition. Our theory predicts, one hand, physical limits tether strength, under tugging set affinity ceiling. On other intriguingly, use force heterogeneity diversify phenotype without compromising fitness, thus remaining plastic resource constraint. results suggest probing receptor quality—via molecular tug war during recognition—limits potency response current antigens, but confer benefit variants. By bridging mechanisms functions, work reveals multifaceted role forces adaptation, rationalizes key dynamics.Received 28 July 2022Revised 31 January 2023Accepted 23 February 2023DOI:https://doi.org/10.1103/PhysRevX.13.021022Published by American Physical Society terms Creative Commons Attribution 4.0 International license. Further distribution must maintain attribution author(s) published article’s title, journal citation, DOI.Published SocietyPhysics Subject Headings (PhySH)Research AreasEvolutionary dynamicsForce sensingNonequilibrium statistical mechanicsPhysics computationStochastic processesPhysical SystemsBiomoleculesCellsCollective dynamicsStochastic dynamical systemsTechniquesBrownian dynamicsFirst passage problemsLangevin algorithmMultiscale modelingStochastic differential equationsBiological PhysicsStatistical PhysicsInterdisciplinary PhysicsPolymers & Soft MatterNonlinear Dynamics