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  • Featured in Physics
  • Open Access

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

Hongda Jiang and Shenshen Wang*

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

  • *shenshen@physics.ucla.edu
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Phys. Rev. X 13, 021022 – Published 10 May, 2023

DOI: https://doi.org/10.1103/PhysRevX.13.021022

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 rapid evolution inside an individual appears ineffective, hitting a modest ceiling of antigen-binding affinity. Only recently, experiments began to reveal that evolving B cells physically extract antigens from presenting cells using active forces, and that the extraction level dictates clonal fitness. These observations challenge the prevailing view that the equilibrium constant of receptor-antigen binding determines selective advantage of a B cell clone. Here, we present a theoretical framework to explore ways in which tug-of-war antigen extraction impacts the quality and diversity of an evolved B cell repertoire. We propose that the apparent “ineffectiveness” of in vivo selection can be a direct consequence of nonequilibrium antigen recognition. Our theory predicts, on the one hand, that the physical limits of antigen tether strength, under tugging forces, set the affinity ceiling. On the other hand, intriguingly, cells can use force heterogeneity 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—limits the potency of response to current antigens, but confer adaptive benefit against future variants. By bridging physical mechanisms and evolved functions, this work reveals a multifaceted role of active forces in immune adaptation, which rationalizes key observations on repertoire dynamics.

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Physics Subject Headings (PhySH)

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The Mechanical Struggle behind Adaptive Immunity

Published 10 May, 2023

A study of the mechanical forces in certain immune cells may give new insights into how organisms deal with ever-evolving pathogens.

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Popular Summary

Biological systems learn by accumulating incremental changes to better suit future environments. The immune system does so through a rapid evolutionary process inside the host that improves antigen recognition on the fly. However, this Darwinian-like process appears surprisingly ineffective—why and how so remains a key puzzle. Recently, immune cells were found to acquire antigens from other cells using active forces, rather than relying on equilibrium binding. Here, we explore whether and when active probing of receptor quality during antigen recognition confers an adaptive benefit. By assessing the macroscopic impact of microscopic dynamics, we show how the nonequilibrium nature of antigen recognition limits the potency of response to current targets and yet enables plasticity against future threats.

Specifically, we present a theoretical framework that bridges the gap between molecular interaction and clonal selection through tug-of-war antigen extraction by cells. This active extraction process is shown to unify multiple in vivo observations and predict new ones: It rationalizes the apparent ineffectiveness of natural selection through a balance between depth and breadth of protection with limited resources, explains low specificity and high diversity of memory cells, and predicts a persistent variety of receptor-antigen binding affinities.

This work proposes a new paradigm of biological recognition via nonequilibrium, physical acquisition of stimuli, which may complement the current view centered on biochemical signaling. Meanwhile, it offers a fresh and informative angle for understanding biological learning in light of physical influences on evolution. Our findings have broad implications for physically modulating immune responses and steering adaptive evolution.

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Phys. Rev. X 13, 021022– Published 10 May, 2023
  • Received 28 July 2022
  • Revised 31 January 2023
  • Accepted 23 February 2023
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