Feinerman, O., Germain, R. N. & Altan-Bonnet, G. Quantitative challenges in understanding ligand discrimination by alpha beta T cells. Mol. Immunol. 45(3), 619–631. https://doi.org/10.1016/j.molimm.2007.03.028 (2008).
Weiss, A. & Littman, D. R. Signal transduction by lymphocyte antigen receptors. Cell 76(2), 263–274. https://doi.org/10.1016/0092-8674(94)90334-4 (1994).
Arstila, T. P. et al. A direct estimate of the human alpha beta T cell receptor diversity. Science 286(5441), 958–961. https://doi.org/10.1126/science.286.5441.958 (1999).
Westermann, J. & Pabst, R. Lymphocyte subsets in the blood: A diagnostic window on the lymphoid system?. Immunol. Today 11, 406–410. https://doi.org/10.1016/0167-5699(90)90160-B (1990).
Altan-Bonnet, G. & Germain, R. N. Modeling T cell antigen discrimination based on feedback control of digital ERK responses. PLoS Biol. 3(11), e356. https://doi.org/10.1371/journal.pbio.0030356 (2005).
Dushek, O. et al. Antigen potency and maximal efficacy reveal a mechanism of efficient T cell activation. Sci. Signal. 4(176), ra39. https://doi.org/10.1126/scisignal.2001430 (2011).
McKeithan, T. W. Kinetic proofreading in T-cell receptor signal transduction. Proc. Natl. Acad. Sci. 92(11), 5042–5046. https://doi.org/10.1073/pnas.92.11.5042 (1995).
Madrenas, J. et al. Zeta phosphorylation without ZAP-70 activation induced by TCR antagonists or partial agonists. Science 267(5197), 515–518. https://doi.org/10.1126/science.7824949 (1995).
Kersh, E. N., Shaw, A. S. & Allen, P. M. Fidelity of T cell activation through multistep T cell receptor zeta phosphorylation. Science 281(5376), 572–575. https://doi.org/10.1126/science.281.5376.572 (1998).
Bongrand, P. & Malissen, B. Quantitative aspects of T-cell recognition: From within the antigen-presenting cell to within the T cell. Bioessays 20(5), 412–422. https://doi.org/10.1002/(SICI)1521-1878(199805)20:5\(<\)412::AID-BIES8\(>\)3.0.CO;2-P (1998).
Sykulev, Y. et al. Evidence that a single peptide-MHC complex on a target cell can elicit a cytolytic T cell response. Immunity 4(6), 565–571. https://doi.org/10.1016/S1074-7613(00)80483-5 (1996).
Valitutti, S. et al. Serial triggering of many T-cell receptors by a few peptide-MHC complexes. Nature 375(6527), 148–151. https://doi.org/10.1038/375148a0 (1995).
Kalergis, A. M. et al. Efficient T cell activation requires an optimal dwell-time of interaction between the TCR and the pMHC complex. Nat. Immunol. 2(3), 229–234. https://doi.org/10.1038/85286 (2001).
Coombs, D. et al. Activated TCRs remain marked for internalization after dissociation from pMHC. Nat. Immunol. 3(10), 926–931. https://doi.org/10.1038/ni838 (2002).
Tian, S. et al. CD8+ T cell activation is governed by TCR-peptide/MHC affinity, not dissociation rate. J. Immunol. 179(5), 2952–2960. https://doi.org/10.4049/jimmunol.179.5.2952 (2007).
Campillo-Davo, D., Flumens, D. & Lion, E. The quest for the best: How TCR affinity, avidity, and functional avidity affect TCR-engineered T-cell antitumor responses. Cells 9(7), 1720. https://doi.org/10.3390/cells9071720 (2020).
Allard, M. et al. TCR-ligand dissociation rate is a robust and stable biomarker of CD8+ T cell potency. JCI Insight 2(14). https://doi.org/10.1172/jci.insight.92570 (2017).
Davis, S. J. & Van Der Merwe, P. A. The kinetic-segregation model: TCR triggering and beyond. Nat. Immunol. 7(8), 803–809. https://doi.org/10.1038/ni1369 (2006).
Lee, S. F. et al. Super-resolution imaging of T cell triggering supports the kinetic segregation model in the adaptive immune response. Biophys. J. 104(2), 428a. https://doi.org/10.1016/j.bpj.2012.11.2382 (2013).
Sasmal, D. K. et al. TCR-pMHC bond conformation controls TCR ligand discrimination. Cell. Mol. Immunol. 17(3), 203–217. https://doi.org/10.1038/s41423-019-0273-6 (2020).
Li, Y.-C. et al. Cutting edge: Mechanical forces acting on T cells immobilized via the TCR complex can trigger TCR signaling. J. Immunol. 184(11), 5959–5963. https://doi.org/10.4049/jimmunol.0900775 (2010).
Ma, Z., Discher, D. E. & Finkel, T. H. Mechanical force in T cell receptor signal initiation. Front. Immunol. 3, 217. https://doi.org/10.3389/fimmu.2012.00217 (2012).
Andersen, P. S. et al. Role of the T cell receptor ligand affinity in T cell activation by bacterial superantigens. J. Biol. Chem. 276(36), 33452–33457. https://doi.org/10.1074/jbc.M103750200 (2001).
Feinberg, M. Complex balancing in general kinetic systems. Arch. Ration. Mech. Anal. 49(3), 187–194. https://doi.org/10.1007/BF00255665 (1972).
Rendall, A. D. & Sontag, E. D. Multiple steady states and the form of response functions to antigen in a model for the initiation of T-cell activation. R. Soc. Open Sci. 4. https://doi.org/10.1098/rsos.170821 (2017).
Feinberg, M. Chemical reaction network structure and the stability of complex isothermal reactors—I. The deficiency zero and deficiency one theorems. Chem. Eng. Sci. 42(10), 2229–2268. https://doi.org/10.1016/0009-2509(87)80099-4 (1987).
Feinberg, M. Multiple steady states for chemical reaction networks of deficiency one. Arch. Ration. Mech. Anal. 132, 371–406. https://doi.org/10.1007/BF00375615 (1995).
Lever, M. et al. Phenotypic models of T cell activation. Nat. Rev. Immunol. 14(9), 619–629. https://doi.org/10.1038/nri3728 (2014).
François, P. et al. Phenotypic model for early T-cell activation displaying sensitivity, specificity, and antagonism. Proc. Natl. Acad. Sci. 110(10), E888–E897. https://doi.org/10.1073/pnas.1300752110 (2013).
Gálvez, J., Galvez, J. J. & Garcia-Penarrubia, P. TCR/pMHC interaction: Phenotypic model for an unsolved enigma. Front. Immunol. 7, 467. https://doi.org/10.3389/fimmu.2016.00467 (2016).
Lever, M. et al. Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose. Proc. Natl. Acad. Sci. 113(43), E6630–E6638. https://doi.org/10.1073/pnas.1608820113 (2016).
Marino, S. et al. A methodology for performing global uncertainty and sensitivity analysis in systems biology. J. Theor. Biol. 254(1), 178–196. https://doi.org/10.1016/j.jtbi.2008.04.011 (2008).
Gálvez, J., Gálvez, J. J. & Garcıa-Peñarrubia, P. Is TCR/pMHC affinity a good estimate of the T-cell response? An answer based on predictions from 12 phenotypic models. Front. Immunol. 10, 349. https://doi.org/10.3389/fimmu.2019.00349 (2019).
Lipniacki, T. et al. Stochastic effects and bistability in T cell receptor signaling. J. Theor. Biol. 254(1), 110–122. https://doi.org/10.1016/j.jtbi.2008.05.001 (2008).
Hartman, P. Ordinary Differential Equations (Birkhäuser, 1982).
Rendall, A. D. Mathematics of the NFAT signalling pathway. SIAM J. Appl. Dyn. Syst. 11, 988–1006. https://doi.org/10.1137/120866488 (2012).
Feinberg, M. The existence and uniqueness of steady states for a class of chemical reaction networks. Arch. Ration. Mech. Anal. 132, 311–370. https://doi.org/10.1007/BF00375614 (1995).
Horn, F. Necessary and sufficient conditions for complex balancing in chemical kinetics. Arch. Ration. Mech. Anal. 49, 172–186. https://doi.org/10.1007/BF00255664 (1972).
Horn, F. & Jackson, R. General mass action kinetics. Arch. Ration. Mech. Anal. 47, 81–116. https://doi.org/10.1007/BF00251225 (1972).
Davis, M. M. et al. Ligand recognition by \(\alpha \beta\) T cell receptors. Annu. Rev. Immunol. 16(1), 523–544. https://doi.org/10.1146/annurev.immunol.16.1.523 (1998).
Alam, S. M. et al. Qualitative and quantitative differences in T cell receptor binding of agonist and antagonist ligands. Immunity 10(2), 227–237. https://doi.org/10.1016/S1074-7613(00)80023-0 (1999).
Huang, J. et al. The kinetics of two-dimensional TCR and pMHC interactions determine T-cell responsiveness. Nature 464(7290), 932–936. https://doi.org/10.1038/nature08944 (2010).
Dushek, O. & Van der Merwe, P. A. An induced rebinding model of antigen discrimination. Trends Immunol. 35(4), 153–158. https://doi.org/10.1016/j.it.2014.02.002 (2014).
Chervin, A. S. et al. The impact of TCR-binding properties and antigen presentation format on T cell responsiveness. J. Immunol. 183(2), 1166–1178. https://doi.org/10.4049/jimmunol.0900054 (2009).
Varma, R. et al. T cell receptor-proximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster. Immunity 25(1), 117–127. https://doi.org/10.1016/j.immuni.2006.04.010 (2006).
Lee, K.-H. et al. The immunological synapse balances T cell receptor signaling and degradation. Science 302(5648), 1218–1222. https://doi.org/10.1126/science.1086507 (2003).
Corse, E. et al. Attenuated T cell responses to a high-potency ligand in vivo. PLoS Biol. 8(9), e1000481. https://doi.org/10.1371/journal.pbio.1000481 (2010).
Irving, M. et al. Interplay between T cell receptor binding kinetics and the level of cognate peptide presented by major histocompatibility complexes governs CD8+ T cell responsiveness. J. Biol. Chem. 287(27), 23068–23078. https://doi.org/10.1074/jbc.M112.357673 (2012).
González, P. A. et al. T cell receptor binding kinetics required for T cell activation depend on the density of cognate ligand on the antigen-presenting cell. Proc. Natl. Acad. Sci. 102(13), 4824–4829. https://doi.org/10.1073/pnas.0500922102 (2005).
Gnanaprakasam, J. R. et al. Asparagine restriction enhances CD8+ T cell metabolic fitness and antitumoral functionality through an NRF2-dependent stress response. Nat. Metab. 5(8), 1423–1439. https://doi.org/10.1038/s42255-023-00856-1 (2023).
McKarns, S. & Schwartz, R. Biphasic regulation of Il2 transcription in CD4+ T cells: Roles for TNF alpha -receptor signaling and chromatin structure. J. Immunol. https://doi.org/10.4049/jimmunol.181.2.1272 (2008).
Tagawa, Y.-I. et al. Bimodal role of endogenous interleukin-6 in concanavalin A-induced hepatitis in mice. J. Leukocyte Biol. 67(1), 90–96. https://doi.org/10.1002/jlb.67.1.90 (2000).
McKay, M. D. Latin hypercube sampling as a tool in uncertainty analysis of computer models. In Proceedings of the 24th Conference on Winter Simulation. 557–564. (1992). https://www.osti.gov/biblio/7196246.
Iman, R. L. & Conover, W.-J. A distribution-free approach to inducing rank correlation among input variables. Commun. Stat.-Simul. Comput. 11(3), 311–334. https://doi.org/10.1080/03610918208812265 (1982).
McKay, M. D., Beckman, R. J. & Conover, W. J. A comparison of three methods for selecting values of input variables in the analysis of output from a computer code. Technometrics 42(1), 55–61. https://doi.org/10.1080/00401706.2000.10485979 (2000).
Blower, S. M. & Dowlatabadi, H. Sensitivity and uncertainty analysis of complex models of disease transmission: An HIV model, as an example. Int. Stat. Rev./Rev. Int. Stat.. 229–243 (1994). https://doi.org/10.2307/1403510.
Fernández-Aguilar, L. M. et al. A story of kinases and adaptors: The role of LCK, ZAP-70 and LAT in switch panel governing T-cell development and activation. Biology 12(9), 1163. https://doi.org/10.3390/biology12091163 (2023).
Hebeisen, M. et al. SHP-1 phosphatase activity counteracts increased T cell receptor affinity. J. Clin. Invest. 123(3), 1044–1056. https://doi.org/10.1172/JCI65325 (2013).
Hou, B. et al. SHP-1 regulates CD8+ T cell effector function but plays a subtle role with SHP-2 in T cell exhaustion due to a stage-specific nonredundant functional relay. J. Immunol. 212(3), 397–409. https://doi.org/10.4049/jimmunol.2300462 (2024).
Voisinne, G. et al. Kinetic proofreading through the multi-step activation of the ZAP70 kinase underlies early T cell ligand discrimination. Nat. Immunol. 23(9), 1355–1364. https://doi.org/10.1038/s41590-022-01288-x (2022).
Klammt, C. et al. T cell receptor dwell times control the kinase activity of Zap70. Nat. Immunol. 16(9), 961–969. https://doi.org/10.1038/ni.3231 (2015).
Pageon, S. V. et al. Functional role of T-cell receptor nanoclusters in signal initiation and antigen discrimination. Proc. Natl. Acad. Sci. 113(37), E5454–E5463. https://doi.org/10.1073/pnas.1607436113 (2016).
Dong, D. et al. Structural basis of assembly of the human T cell receptor-CD3 complex. Nature 573(7775), 546–552. https://doi.org/10.1038/s41586-019-1537-0 (2019).
Bali, Y., Rendall, A. & Quapp, W. Mechanochemical energy landscapes under force: Catch-slip bonds in T-cell activation. bioRxiv. 2025–11 (2025). https://doi.org/10.1101/2025.11.15.688643.
Rabinowitz, J. D. et al. Kinetic discrimination in T-cell activation. Proc. Natl. Acad. Sci. 93(4), 1401–1405. https://doi.org/10.1073/pnas.93.4.1401 (1996).
Matis, L. A. et al. Magnitude of response of histocompatibility-restricted T-cell clones is a function of the product of the concentrations of antigen and Ia molecules. Proc. Natl. Acad. Sci. 80(19), 6019–6023. https://doi.org/10.1073/pnas.80.19.6019 (1983).


















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