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  • Open Access

Adaptive Mechanical Proofreading Toward Robust yet Tunable Humoral Immunity

Qing Xu, Hongda Jiang, and Shenshen Wang*

  • *Contact author: shenshen@physics.ucla.edu
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PRX Life 4, 023007 – Published 17 April, 2026

DOI: https://doi.org/10.1103/vfqt-t3b9

Abstract

To reliably transmit information, cells exploit nonequilibrium drives to reduce errors. Kinetic proofreading is a classic mechanism that sharpens ligand discrimination by T lymphocytes, yet it remains unclear whether adaptive immunity relies on kinetic proofreading alone to achieve high fidelity. Here, we propose an alternative: an enhanced form of mechanical proofreading (MPR), in which adaptive force generation during dynamic cell-cell contact enables faithful selection of high-affinity B lymphocytes. Using a coarse-grained model validated by experiments, we show that adaptive MPR, characterized by mechanical feedback between force exertion and contact formation, supports robust discrimination of receptor quality regardless of ligand quantity. While MPR generally balances tradeoffs between speed and fidelity, a negative scaling of contact duration with ligand abundance reveals the presence of feedback. By modulating interactions among distinct ligands that share mechanical load at membrane contacts, adaptive MPR may help mitigate autoimmunity or enhance multivalent vaccines. Overall, this work generalizes proofreading to include cellular designs that operate across scales to reconcile competing functional demands at the systems level.

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PRX Life Collection on adaptation and learning

PRX Life presents a special collection on ‘Biological systems that learn’, curated by the organizers of the National Institute for Theory and Mathematics in Biology (NITMB) workshop together with early-career researchers. The papers in this collection illustrate how living systems acquire functions, showing it is useful to describe them as tunable matter with many individually adjustable degrees of freedom characterizing microscopic properties. Drawing inspiration from AI and non-biological systems that can acquire desired functions, the featured research highlights the timeliness of the topic and its potential to drive unifying frameworks for emergent collective function in living tunable matter.

Every article in this collection is subject to a rigorous peer review process, upholding the high standards applied to all papers in the journal. The PRX Life editorial team manages peer review and makes all editorial decisions.

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References (59)

  1. J. Ninio, Kinetic amplification of enzyme discrimination, Biochimie 57, 587 (1975).
  2. J. J. Hopfield, Kinetic proofreading: a new mechanism for reducing errors in biosynthetic processes requiring high specificity, Proc. Natl. Acad. Sci. USA 71, 4135 (1974).
  3. M. Ehrenberg and C. Blomberg, Thermodynamic constraints on kinetic proofreading in biosynthetic pathways, Biophys. J. 31, 333 (1980).
  4. A. Murugan, D. A. Huse, and S. Leibler, Discriminatory proofreading regimes in nonequilibrium systems, Phys. Rev. X 4, 021016 (2014).
  5. T. W. McKeithan, Kinetic proofreading in t-cell receptor signal transduction, Proc. Natl. Acad. Sci. USA 92, 5042 (1995).
  6. R. Phillips, The Molecular Switch: Signaling and Allostery (Princeton University Press, Princeton, NJ, 2020).
  7. E. Natkanski, W.-Y. Lee, B. Mistry, A. Casal, J. E. Molloy, and P. Tolar, B cells use mechanical energy to discriminate antigen affinities, Science 340, 1587 (2013).
  8. K. Suzuki, I. Grigorova, T. G. Phan, L. M. Kelly, and J. G. Cyster, Visualizing B cell capture of cognate antigen from follicular dendritic cells, J. Exp. Med. 206, 1485 (2009).
  9. H. N. Eisen and G. W. Siskind, Variations in affinities of antibodies during the immune response, Biochemistry 3, 996 (1964).
  10. G. D. Victora and M. C. Nussenzweig, Germinal centers, Annu. Rev. Immunol. 30, 429 (2012).
  11. G. D. Victora and M. C. Nussenzweig, Germinal centers, Annu. Rev. Immunol. 40, 413 (2022).
  12. F. D. Batista, D. Iber, and M. S. Neuberger, B cells acquire antigen from target cells after synapse formation, Nature (London) 411, 489 (2001).
  13. H. C. W. McArthur, A. T. Bajur, M. Iliopoulou, and K. M. Spillane, Antigen mobility regulates the dynamics and precision of antigen capture in the B cell immune synapse, Proc. Natl. Acad. Sci. USA 122, e2422528122 (2025).
  14. A. Lanzavecchia, Antigen-specific interaction between T and B cells, Nature (London) 314, 537 (1985).
  15. G. D. Victora, T. A. Schwickert, D. R. Fooksman, A. O. Kamphorst, M. Meyer-Hermann, M. L. Dustin, and M. C. Nussenzweig, Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter, Cell 143, 592 (2010).
  16. H. Jiang and S. Wang, Immune cells use active tugging forces to distinguish affinity and accelerate evolution, Proc. Natl. Acad. Sci. USA 120, e2213067120 (2023).
  17. H. Jiang and S. Wang, Molecular tug of war reveals adaptive potential of an immune cell repertoire, Phys. Rev. X 13, 021022 (2023).
  18. H. Jiang and S. Wang, Physical extraction of antigen and information, Proc. Natl. Acad. Sci. USA 121, e2320537121 (2024).
  19. C. R. Nowosad, K. M. Spillane, and P. Tolar, Germinal center B cells recognize antigen through a specialized immune synapse architecture, Nat. Immunol. 17, 870 (2016).
  20. J. Wang, F. Lin, Z. Wan, X. Sun, Y. Lu, J. Huang, F. Wang, Y. Zeng, Y.-H. Chen, Y. Shi, W. Zheng, Z. Li, C. Xiong, and W. Liu, Profiling the origin, dynamics, and function of traction force in B cell activation, Sci. Signaling 11, eaai9192 (2018).
  21. M. Knežević, H. Jiang, and S. Wang, Active tuning of synaptic patterns enhances immune discrimination, Phys. Rev. Lett. 121, 238101 (2018).
  22. G. I. Bell, Models for the specific adhesion of cells to cells, Science 200, 618 (1978).
  23. F. M. Mason and A. C. Martin, Tuning cell shape change with contractile ratchets, Curr. Opin. Genet. Dev. 21, 671 (2011).
  24. J. E. Komianos and G. A. Papoian, Stochastic ratcheting on a funneled energy landscape is necessary for highly efficient contractility of actomyosin force dipoles, Phys. Rev. X 8, 021006 (2018).
  25. F. D. Batista and M. S. Neuberger, B cells extract and present immobilized antigen: implications for affinity discrimination, EMBO J. 19, 513 (2000).
  26. C. D. C. Allen, T. Okada, H. L. Tang, and J. G. Cyster, Imaging of germinal center selection events during affinity maturation, Science 315, 528 (2007).
  27. K. Kwak, N. Quizon, H. Sohn, A. Saniee, J. Manzella-Lapeira, P. Holla, J. Brzostowski, J. Lu, H. Y. Xie, C. Xu, K. M. Spillane, P. Tolar, and S. K. Pierce, Intrinsic properties of human germinal center B cells set antigen affinity thresholds, Sci. Immunol. 3, eaau6598 (2018).
  28. K. M. Spillane and P. Tolar, B cell antigen extraction is regulated by physical properties of antigen presenting cells, Biophys. J. 112, 126a (2017).
  29. See Supplemental Material at http://link.aps.org/supplemental/10.1103/vfqt-t3b9 for details of the bifurcation analysis and stochastic simulations, calculation of the scaling relationship of contact duration with ligand quantity, description of the readout distribution and its moments, analysis of conditional distributions of contact duration, and characterization of absolute discrimination, which includes Refs. [54, 55, 56, 57, 58].
  30. T. Wong, T. Chou, S. Shankar, and S. Wang, Mechanical activity enables patterning and discrimination at the immune synapse, arXiv:2510.18771.
  31. A. D. Gitlin, Z. Shulman, and M. C. Nussenzweig, Clonal selection in the germinal centre by regulated proliferation and hypermutation, Nature (London) 509, 637 (2014).
  32. B. Wang and O. K. Dudko, A theory of synaptic transmission, eLife 10, e73585 (2021).
  33. W. Cui and P. Mehta, Identifying feasible operating regimes for early T-cell recognition: The speed, energy, accuracy trade-off in kinetic proofreading and adaptive sorting, PLoS One 13, e0202331 (2018).
  34. O. Shoval, H. Sheftel, G. Shinar, Y. Hart, O. Ramote, A. Mayo, E. Dekel, K. Kavanagh, and U. Alon, Evolutionary trade-offs, pareto optimality, and the geometry of phenotype space, Science 336, 1157 (2012).
  35. G. Altan-Bonnet and R. N. Germain, Modeling t cell antigen discrimination based on feedback control of digital erk responses, PLoS Biol. 3, e356 (2005).
  36. O. Feinerman, R. N. Germain, and G. Altan-Bonnet, Quantitative challenges in understanding ligand discrimination by αβ T cells, Mol. Immunol. 45, 619 (2008), Special section: Theories and Modelling of T Cell Behaviour.
  37. P. François, G. Voisinne, E. D. Siggia, G. Altan-Bonnet, and M. Vergassola, Phenotypic model for early T-cell activation displaying sensitivity, specificity, and antagonism, Proc. Natl. Acad. Sci. USA 110, E888 (2013).
  38. P. François and G. Altan-Bonnet, The case for absolute ligand discrimination: Modeling information processing and decision by immune T cells, J. Stat. Phys. 162, 1130 (2016).
  39. A. Martinez-Riano, S. Wang, S. Boeing, S. Minoughan, A. Casal, K. M. Spillane, B. Ludewig, and P. Tolar, Long-term retention of antigens in germinal centers is controlled by the spatial organization of the follicular dendritic cell network, Nat. Immunol. 24, 1281 (2023).
  40. J. W. Schrader, Antagonism of B lymphocyte mitogenesis by anti-immunoglobulin antibody, J. Immunol. 115, 323 (1975).
  41. J. F. Kearney, M. D. Cooper, and A. R. Lawton, B lymphocyte differentiation induced by lipopolysaccharide: III. Suppression of B cell maturation by anti-mouse immunoglobulin antibodies, J. Immunol. 116, 1664 (1976).
  42. S. C. Jameson and M. J. Bevan, T cell receptor antagonists and partial agonists, Immunity 2, 1 (1995).
  43. J. Ruppert, J. Alexander, K. Snoke, M. Coggeshall, E. Herbert, D. McKenzie, H. M. Grey, and A. Sette, Effect of T-cell receptor antagonism on interaction between T cells and antigen-presenting cells and on T-cell signaling events, Proc. Natl. Acad. Sci. USA 90, 2671 (1993).
  44. P. Klenerman, S. Rowland-Jones, S. McAdam, J. Edwards, S. Daenke, D. Lalloo, B. Köppe, W. Rosenberg, D. Boyd, A. Edwards, et al., Cytotoxic T-cell activity antagonized by naturally occurring HIV-1 gag variants, Nature (London) 369, 403 (1994).
  45. U.-C. Meier, P. Klenerman, P. Griffin, W. James, B. Köppe, B. Larder, A. McMichael, and R. Phillips, Cytotoxic T lymphocyte lysis inhibited by viable HIV mutants, Science 270, 1360 (1995).
  46. T. N. Schumacher and R. D. Schreiber, Neoantigens in cancer immunotherapy, Science 348, 69 (2015).
  47. S. J. Kent, P. D. Greenberg, M. C. Hoffman, R. E. Akridge, and M. J. McElrath, Antagonism of vaccine-induced HIV-1-specific CD4 T cells by primary HIV-1 infection: potential mechanism of vaccine failure, J. Immunol. 158, 807 (1997).
  48. B. Vanhove, N. Poirier, F. Fakhouri, L. Laurent, B. 't Hart, P. H. Papotto, L. V. Rizzo, M. Zaitsu, F. Issa, K. Wood, et al., Antagonist anti-CD28 therapeutics for the treatment of autoimmune disorders, Antibodies 6, 19 (2017).
  49. T. J. Rademaker, E. Bengio, and P. François, Attack and defense in cellular decision-making: Lessons from machine learning, Phys. Rev. X 9, 031012 (2019).
  50. Z. Sabouri, P. Schofield, K. Horikawa, E. Spierings, D. Kipling, K. L. Randall, D. Langley, B. Roome, R. Vazquez-Lombardi, R. Rouet, et al., Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity, Proc. Natl. Acad. Sci. USA 111, E2567 (2014).
  51. J. H. Reed, J. Jackson, D. Christ, and C. C. Goodnow, Clonal redemption of autoantibodies by somatic hypermutation away from self-reactivity during human immunization, J. Exp. Med. 213, 1255 (2016).
  52. D. L. Burnett, J. H. Reed, D. Christ, and C. C. Goodnow, Clonal redemption and clonal anergy as mechanisms to balance B cell tolerance and immunity, Immunol. Rev. 292, 61 (2019).
  53. R. Morán-Tovar and M. Lässig, Nonequilibrium antigen recognition during infections and vaccinations, Phys. Rev. X 14, 031026 (2024).
  54. D. T. Gillespie, Exact stochastic simulation of coupled chemical reactions, J. Phys. Chem. 81, 2340 (1977).
  55. D. F. Anderson, A modified next reaction method for simulating chemical systems with time dependent propensities and delays, J. Chem. Phys. 127, 214107 (2007).
  56. K. M. Spillane and P. Tolar, B cell antigen extraction is regulated by physical properties of antigen-presenting cells, J. Cell Biol. 216, 217 (2017).
  57. S. K. Norman, L. Johnson, and A. W. Kemp, Univariate Discrete Distributions (John Wiley & Sons, Hoboken, NJ, 2005).
  58. R. Eisinga, M. Grotenhuis, and B. Pelzer, Saddlepoint approximation for the sum of independent non-identically distributed binomial random variables, Stat. Neerl. 67, 190 (2013).
  59. Q. Xu, sunchi7/Adaptive-MPR, https://github.com/sunchi7/Adaptive-MPR.

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PRX Life 4, 023007– Published 17 April, 2026
  • Received 23 August 2025
  • Accepted 13 March 2026
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Published by the American Physical Society under the terms of the Creative Commons Attribution 4.0 International license. Further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation, and DOI.

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