Key Points
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T cell receptor (TCR) stimulation, a series of biochemical signalling reactions, must occur for T cells to become activated. These biochemical processes involve dynamic, stochastic and cooperative events involving many proteins. They occur over multiple timescales and take place in the membrane, cytoplasm and nucleus. The complexity of these dynamic processes can make it difficult to intuit mechanistic principles from experimental observations. We describe why and how computational and theoretical approaches can complement experiments to aid the elucidation of such mechanistic principles.
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If a detailed conceptual model of a signalling module and measurements of various rate parameters and protein concentrations are available, a computational model can convert this knowledge into a quantitative predictive tool. More importantly, when such a detailed picture is not available, theoretical and computational analyses can complement experiments to identify possible mechanisms for a new phenomenon, and thereby reveal new aspects of the T cell signalling pathway. This is because computational models can be used to eliminate hypotheses that are inconsistent with known facts, reveal gaps in our knowledge of the signalling pathway and design experiments that can discriminate between viable hypotheses.
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Different theoretical and computational approaches are described, with special emphasis on the differences between them, the suitability of each approach for answering different types of biological questions and how information obtained from them can complement specific types of experimental studies.
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Examples of successes emerging from studies wherein experimental and computational approaches are used in a complementary manner are described. Attention is devoted to studies that determine how feedback loops in the T cell signalling pathway regulate cellular responses (such as digital signalling and ligand discrimination) and how spatial organization of membrane-associated signalling components influence the earliest events in T cell signalling. Some potentially fruitful future directions of research are noted.
Abstract
T cells are activated when extracellular stimuli, such as a ligand binding to the T cell receptor, are converted into functional outputs by the T cell signalling network. T cell receptor signalling is a highly complex, stochastic and dynamic process involving many interacting proteins. This complexity often confounds intuition, making it difficult to develop mechanistic principles that underly experimental observations. In this Review, we describe how computational approaches can partner successfully with biological experimentation to help address this challenge, and we illustrate this paradigm by summarizing recent work that shows new aspects of the T cell signalling network.
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References
Allison, J. P., Mcintyre, B. W. & Bloch, D. Tumor-specific antigen of murine T-lymphoma defined with monoclonal-antibody. J. Immunol. 129, 2293–2300 (1982).
Chan, A. C., Iwashima, M., Turck, C. W. & Weiss, A. Zap-70 — a 70 Kd protein-tyrosine kinase that associates with the TCR ζ-chain. Cell 71, 649–662 (1992).
Dialynas, D. P. et al. Characterization of the murine antigenic determinant, designated L3T4a, recognized by monoclonal-antibody GK1.5 — expression of L3T4a by functional T-cell clones appears to correlate primarily with class II MHC antigen-reactivity. Immunol. Rev. 74, 29–56 (1983).
Gallegos, A. M. & Bevan, M. J. Central tolerance: good but imperfect. Immunol. Rev. 209, 290–296 (2006).
Hedrick, S. M., Cohen, D. I., Nielsen, E. A. & Davis, M. M. Isolation of cDNA clones encoding T cell-specific membrane-associated proteins. Nature 308, 149–153 (1984).
Hogquist, K. A., Baldwin, T. A. & Jameson, S. C. Central tolerance: learning self-control in the thymus. Nature Rev. Immunol. 5, 772–782 (2005).
Irving, B. A. & Weiss, A. The cytoplasmic domain of the T cell receptor ζ chain is sufficient to couple to receptor-associated signal transduction pathways. Cell 64, 891–901 (1991).
Kung, P., Goldstein, G., Reinherz, E. L. & Schlossman, S. F. Monoclonal antibodies defining distinctive human T cell surface antigens. Science 206, 347–349 (1979).
Unanue, E. R. Antigen-presenting function of the macrophage. Annu. Rev. Immunol. 2, 395–428 (1984).
Yanagi, Y. et al. A human T cell-specific cDNA clone encodes a protein having extensive homology to immunoglobulin chains. Nature 308, 145–149 (1984).
Chen, K. C. et al. Integrative analysis of cell cycle control in budding yeast. Mol. Biol. Cell 15, 3841–3862 (2004).
Mello, B. A. & Tu, Y. Effects of adaptation in maintaining high sensitivity over a wide range of backgrounds for Escherichia coli chemotaxis. Biophys. J. 92, 2329–2337 (2007).
Daniels, B. C., Chen, Y. J., Sethna, J. P., Gutenkunst, R. N. & Myers, C. R. Sloppiness, robustness, and evolvability in systems biology. Curr. Opin. Biotechnol. 19, 389–395 (2008). In this paper, the sensitivity and robustness of biological networks to variation in parameters for various networks are reviewed.
Barkai, N. & Leibler, S. Robustness in simple biochemical networks. Nature 387, 913–917 (1997).
von Dassow, G., Meir, E., Munro, E. M. & Odell, G. M. The segment polarity network is a robust developmental module. Nature 406, 188–192 (2000).
Germain, R. N. The art of the probable: system control in the adaptive immune system. Science 293, 240–245 (2001).
Battogtokh, D., Asch, D. K., Case, M. E., Arnold, J. & Schuttler, H. B. An ensemble method for identifying regulatory circuits with special reference to the qa gene cluster of Neurospora crassa. Proc. Natl Acad. Sci. USA 99, 16904–16909 (2002).
Apgar, J. F., Toettcher, J. E., Endy, D., White, F. M. & Tidor, B. Stimulus design for model selection and validation in cell signaling. PLoS Comput. Biol. 4, e30 (2008).
Das, J. et al. Digital signaling and hysteresis characterize Ras activation in lymphoid cells. Cell 136, 337–351 (2009). Complementary experimental and computational approaches were used to study the mechanism of RAS activation in lymphocytes and the concomitant hysteresis, which may confer T cells with short-term memory of past encounters with antigen.
McAdams, H. H. & Arkin, A. Stochastic mechanisms in gene expression. Proc. Natl Acad. Sci. USA 94, 814–819 (1997).
Elowitz, M. B., Levine, A. J., Siggia, E. D. & Swain, P. S. Stochastic gene expression in a single cell. Science 297, 1183–1186 (2002).
Mosmann, T. R. & Coffman, R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145–173 (1989).
Fathman, C. G. & Lineberry, N. B. Molecular mechanisms of CD4+ T-cell anergy. Nature Rev. Immunol. 7, 599–609 (2007).
Reth, M. & Brummer, T. Feedback regulation of lymphocyte signalling. Nature Rev. Immunol. 4, 269–277 (2004). This paper provides a review of feedback regulation in lymphocyte signalling.
Acuto, O., Bartolo, V. D. & Michel, F. Tailoring T-cell receptor signals by proximal negative feedback mechanisms. Nature Rev. Immunol. 8, 699–712 (2008).
Altan-Bonnet, G. & Germain, R. N. Modeling T cell antigen discrimination based on feedback control of digital ERK responses. PLoS Biol. 3, e356 (2005). In this report, complementary experimental and theoretical approaches are used to study the importance of positive and negative feedback regulation of LCK for ligand discrimination.
Genot, E. & Cantrell, D. A. Ras regulation and function in lymphocytes. Curr. Opin. Immunol. 12, 289–294 (2000).
Mor, A. & Philips, M. R. Compartmentalized Ras/MAPK signaling. Annu. Rev. Immunol. 24, 771–800 (2006).
Roose, J. P., Mollenauer, M., Gupta, V. A., Stone, J. & Weiss, A. A diacylglycerol-protein kinase C-RasGRP1 pathway directs Ras activation upon antigen receptor stimulation of T cells. Mol. Cell. Biol. 25, 4426–4441 (2005).
Roose, J. P., Mollenauer, M., Ho, M., Kurosaki, T. & Weiss, A. Unusual interplay of two types of Ras activators, RasGRP and SOS, establishes sensitive and robust Ras activation in lymphocytes. Mol. Cell. Biol. 27, 2732–2745 (2007). This paper describes how two RASGEFs have a role in activating RAS in lymphocytes.
Corbalan-Garcia, S., Margarit, S. M., Galron, D., Yang, S. S. & Bar-Sagi, D. Regulation of Sos activity by intramolecular interactions. Mol. Cell. Biol. 18, 880–886 (1998).
Margarit, S. M. et al. Structural evidence for feedback activation by Ras.GTP of the Ras-specific nucleotide exchange factor SOS. Cell 112, 685–695 (2003). Using crystallographic techniques, this paper was the first to show the existence of an allosteric site in the enzyme SOS that mediates positive feedback regulation of RAS activation.
Sondermann, H. et al. Structural analysis of autoinhibition in the Ras activator Son of sevenless. Cell 119, 393–405 (2004).
Zhang, W., Sloan-Lancaster, J., Kitchen, J., Trible, R. P. & Samelson, L. E. LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell 92, 83–92 (1998).
Gureasko, J. et al. Membrane-dependent signal integration by the Ras activator Son of sevenless. Nature Struct. Mol. Biol. 15, 452–461 (2008).
Ferrell, J. E. Jr. Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability. Curr. Opin. Cell Biol. 14, 140–148 (2002). This is a comprehensive review of the influence of feedback regulation and bistability in cell signalling.
Irvine, D. J., Purbhoo, M. A., Krogsgaard, M. & Davis, M. M. Direct observation of ligand recognition by T cells. Nature 419, 845–849 (2002).
Gillespie, D. T. Exact stochastic simulation of coupled chemical-reactions. J. Phys. Chem. 81, 2340–2361 (1977). This paper describes a simple algorithm to carry out exact stochastic simulations of chemical reactions that is now used extensively in computational studies.
Henrickson, S. E. et al. T cell sensing of antigen dose governs interactive behavior with dendritic cells and sets a threshold for T cell activation. Nature Immunol. 9, 282–291 (2008).
Feinerman, O., Veiga, J., Dorfman, J. R., Germain, R. N. & Altan-Bonnet, G. Variability and robustness in T cell activation from regulated heterogeneity in protein levels. Science 321, 1081–1084 (2008).
Stefanova, I. et al. TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nature Immunol. 4, 248–254 (2003).
Li, Q. J. et al. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129, 147–161 (2007).
Colman-Lerner, A. et al. Regulated cell-to-cell variation in a cell-fate decision system. Nature 437, 699–706 (2005).
Spencer, S. L., Gaudet, S., Albeck, J. G., Burke, J. M. & Sorger, P. K. Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. Nature 459, 428–432 (2009).
Lipniacki, T., Hat, B., Faeder, J. R. & Hlavacek, W. S. Stochastic effects and bistability in T cell receptor signaling. J. Theor. Biol. 254, 110–122 (2008).
Alarcon, B., Swamy, M., van Santen, H. M. & Schamel, W. W. T-cell antigen-receptor stoichiometry: pre-clustering for sensitivity. EMBO Rep. 7, 490–495 (2006).
Lillemeier, B. F., Pfeiffer, J. R., Surviladze, Z., Wilson, B. S. & Davis, M. M. Plasma membrane-associated proteins are clustered into islands attached to the cytoskeleton. Proc. Natl Acad. Sci. USA 103, 18992–18997 (2006).
Varma, R., Campi, G., Yokosuka, T., Saito, T. & Dustin, M. L. T cell receptor-proximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster. Immunity 25, 117–127 (2006).
Yokosuka, T. et al. Newly generated T cell receptor microclusters initiate and sustain T cell activation by recruitment of Zap70 and SLP-76. Nature Immunol. 6, 1253–1262 (2005).
Monks, C. R., Freiberg, B. A., Kupfer, H., Sciaky, N. & Kupfer, A. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395, 82–86 (1998).
Grakoui, A. et al. The immunological synapse: a molecular machine controlling T cell activation. Science 285, 221–227 (1999). References 50 and 51 describe the first observations of the immunological synapse.
Valitutti, S., Muller, S., Cella, M., Padovan, E. & Lanzavecchia, A. Serial triggering of many T-cell receptors by a few peptide-MHC complexes. Nature 375, 148–151 (1995). In this paper the serial triggering mechanism for TCR signalling was first proposed.
Coombs, D., Kalergis, A. M., Nathenson, S. G., Wofsy, C. & Goldstein, B. Activated TCRs remain marked for internalization after dissociation from pMHC. Nature Immunol. 3, 926–931 (2002). This paper describes a computational and experimental study of the interplay between serial triggering and kinetic proofreading in TCR activation.
McKeithan, T. W. Kinetic proofreading in T-cell receptor signal transduction. Proc. Natl Acad. Sci. USA 92, 5042–5046 (1995).
Hopfield, J. J. Kinetic proofreading: a new mechanism for reducing errors in biosynthetic processes requiring high specificity. Proc. Natl Acad. Sci. USA 71, 4135–4139 (1974). References 54 and 55 pioneered the concept of kinetic proofreading and its application to TCR signalling.
Holler, P. D., Lim, A. R., Cho, B. K., Rund, L. A. & Kranz, D. M. CD8− T cell transfectants that express a high affinity T cell receptor exhibit enhanced peptide-dependent activation. J. Exp. Med. 194, 1043–1052 (2001).
Wofsy, C., Coombs, D. & Goldstein, B. Calculations show substantial serial engagement of T cell receptors. Biophys. J. 80, 606–612 (2001).
Hlavacek, W. S., Redondo, A., Metzger, H., Wofsy, C. & Goldstein, B. Kinetic proofreading models for cell signaling predict ways to escape kinetic proofreading. Proc. Natl Acad. Sci. USA 98, 7295–7300 (2001).
Goldstein, B., Faeder, J. R. & Hlavacek, W. S. Mathematical and computational models of immune-receptor signalling. Nature Rev. Immunol. 4, 445–456 (2004). This is a comprehensive review of computational models of initiation of immune receptor signalling.
Goldstein, B., Coombs, D., Faeder, J. R. & Hlavacek, W. S. Kinetic proofreading model. Adv. Exp. Med. Biol. 640, 82–94 (2008).
Kirschner, D. E., Chang, S. T., Riggs, T. W., Perry, N. & Linderman, J. J. Toward a multiscale model of antigen presentation in immunity. Immunol. Rev. 216, 93–118 (2007).
Sykulev, Y., Joo, M., Vturina, I., Tsomides, T. J. & Eisen, H. N. Evidence that a single peptide-MHC complex on a target cell can elicit a cytolytic T cell response. Immunity 4, 565–571 (1996).
Krogsgaard, M. et al. Agonist/endogenous peptide-MHC heterodimers drive T cell activation and sensitivity. Nature 434, 238–243 (2005).
Li, Q. J. et al. CD4 enhances T cell sensitivity to antigen by coordinating Lck accumulation at the immunological synapse. Nature Immunol. 5, 791–799 (2004). Complementary experimental and computational studies were used to explore the mechanisms underlying the sensitivity of T cells to minute numbers of agonist ligands.
Yachi, P. P., Ampudia, J., Gascoigne, N. R. & Zal, T. Nonstimulatory peptides contribute to antigen-induced CD8-T cell receptor interaction at the immunological synapse. Nature Immunol. 6, 785–792 (2005).
Wylie, D. C., Das, J. & Chakraborty, A. K. Sensitivity of T cells to antigen and antagonism emerges from differential regulation of the same molecular signaling module. Proc. Natl Acad. Sci. USA 104, 5533–5538 (2007).
Davis, S. J. & van der Merwe, P. A. The kinetic-segregation model: TCR triggering and beyond. Nature Immunol. 7, 803–809 (2006). This paper proposed kinetic segregation as a mechanism for TCR signalling.
Choudhuri, K., Wiseman, D., Brown, M. H., Gould, K. & van der Merwe, P. A. T-cell receptor triggering is critically dependent on the dimensions of its peptide-MHC ligand. Nature 436, 578–582 (2005).
Burroughs, N. J., Lazic, Z. & van der Merwe, P. A. Ligand detection and discrimination by spatial relocalization: a kinase–phosphatase segregation model of TCR activation. Biophys. J. 91, 1619–1629 (2006). A computational study of the kinetic segregation model.
Burroughs, N. J. & van der Merwe, P. A. Stochasticity and spatial heterogeneity in T-cell activation. Immunol. Rev. 216, 69–80 (2007).
Huppa, J. B. & Davis, M. M. T-cell-antigen recognition and the immunological synapse. Nature Rev. Immunol. 3, 973–983 (2003).
Huse, M., Lillemeier, B. F., Kuhns, M. S., Chen, D. S. & Davis, M. M. T cells use two directionally distinct pathways for cytokine secretion. Nature Immunol. 7, 247–255 (2006).
Chang, J. T. et al. Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science 315, 1687–1691 (2007).
Lee, K. H. et al. T cell receptor signaling precedes immunological synapse formation. Science 295, 1539–1542 (2002).
Lee, K. H. et al. The immunological synapse balances T cell receptor signaling and degradation. Science 302, 1218–1222 (2003). In this report, complementary computational and experimental approaches were used to dissect signalling in the immunological synapse.
Dushek, O. & Coombs, D. Analysis of serial engagement and peptide–MHC transport in T cell receptor microclusters. Biophys. J. 94, 3447–3460 (2008).
Cemerski, S. et al. The stimulatory potency of T cell antigens is influenced by the formation of the immunological synapse. Immunity 26, 345–355 (2007).
Cemerski, S. et al. The balance between T cell receptor signaling and degradation at the center of the immunological synapse is determined by antigen quality. Immunity 29, 414–422 (2008).
Huppa, J. B., Gleimer, M., Sumen, C. & Davis, M. M. Continuous T cell receptor signaling required for synapse maintenance and full effector potential. Nature Immunol. 4, 749–755 (2003).
Yokosuka, T. et al. Spatiotemporal regulation of T cell costimulation by TCR–CD28 microclusters and protein kinase Cθ translocation. Immunity 29, 589–601 (2008).
Bhalla, U. S. & Iyengar, R. Emergent properties of networks of biological signaling pathways. Science 283, 381–387 (1999).
Daniels, M. A. et al. Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature 444, 724–729 (2006).
Gilbert, J. J. et al. Antigen receptors on immature, but not mature, B and T cells are coupled to cytosolic phospholipase A2 activation: expression and activation of cytosolic phospholipase A2 correlate with lymphocyte maturation. J. Immunol. 156, 2054–2061 (1996).
Gunawardena, J. Multisite protein phosphorylation makes a good threshold but can be a poor switch. Proc. Natl Acad. Sci. USA 102, 14617–14622 (2005).
Huang, C. Y. & Ferrell, J. E., Jr. Ultrasensitivity in the mitogen-activated protein kinase cascade. Proc. Natl Acad. Sci. USA 93, 10078–10083 (1996).
Markevich, N. I., Hoek, J. B. & Kholodenko, B. N. Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades. J. Cell Biol. 164, 353–359 (2004).
Prasad, A. et al. Origin of the sharp boundary that discriminates positive and negative selection of thymocytes. Proc. Natl Acad. Sci. USA 106, 528–533 (2009).
Aivazian, D. & Stern, L. J. Phosphorylation of T cell receptor ζ is regulated by a lipid dependent folding transition. Nature Struct. Biol. 7, 1023–1026 (2000).
Xu, C. et al. Regulation of T cell receptor activation by dynamic membrane binding of the CD3ɛ cytoplasmic tyrosine-based motif. Cell 135, 702–713 (2008).
Mor, A. et al. The lymphocyte function-associated antigen-1 receptor costimulates plasma membrane Ras via phospholipase D2. Nat. Cell Biol. 9, 713–719 (2007).
Tian, T. et al. Plasma membrane nanoswitches generate high-fidelity Ras signal transduction. Nat. Cell Biol. 9, 905–914 (2007).
Plyasunov, S. & Arkin, A. P. Efficient stochastic sensitivity analysis of discrete event systems. J. Comput. Phys. 221, 724–738 (2007).
Lis, M., Artyomov, M. N., Devadas, S. & Chakraborty, A. K. Efficient stochastic simulation of reaction-diffusion processes via direct compilation. Bioinformatics 25, 2289–2291 (2009).
Blinov, M. L., Faeder, J. R., Goldstein, B. & Hlavacek, W. S. A network model of early events in epidermal growth factor receptor signaling that accounts for combinatorial complexity. Biosystems 83, 136–151 (2006).
Meier-Schellersheim, M. et al. Key role of local regulation in chemosensing revealed by a new molecular interaction-based modeling method. PLoS Comput. Biol. 2, e82 (2006).
Slepchenko, B. M., Schaff, J. C., Macara, I. & Loew, L. M. Quantitative cell biology with the Virtual Cell. Trends Cell Biol. 13, 570–576 (2003).
Hlavacek, W. S. et al. Rules for modeling signal-transduction systems. Sci. STKE 2006, re6 (2006). References 93–97 describe user-friendly computer codes that can be used to simulate lymphocyte signalling processes.
Kholodenko, B. N. Cell-signalling dynamics in time and space. Nature Rev. Mol. Cell Biol. 7, 165–176 (2006). An informative review on spatio-temporal dynamics in cell signalling processes.
Arkin, A., Ross, J. & McAdams, H. H. Stochastic kinetic analysis of developmental pathway bifurcation in phage λ-infected Escherichia coli cells. Genetics 149, 1633–1648 (1998).
Gillespie, D. T. Stochastic simulation of chemical kinetics. Annu. Rev. Phys. Chem. 58, 35–55 (2007).
Allen, R. J., Warren, P. B. & Ten Wolde, P. R. Sampling rare switching events in biochemical networks. Phys. Rev. Lett. 94, 018104 (2005).
Janes, K. A. et al. A systems model of signaling identifies a molecular basis set for cytokine-induced apoptosis. Science 310, 1646–1653 (2005).
Janes, K. A. & Yaffe, M. B. Data-driven modelling of signal-transduction networks. Nature Rev. Mol. Cell Biol. 7, 820–828 (2006).
Saez-Rodriguez, J. et al. A logical model provides insights into T cell receptor signaling. PLoS Comput. Biol. 3, e163 (2007).
Zhang, R. et al. Network model of survival signaling in large granular lymphocyte leukemia. Proc. Natl Acad. Sci. USA 105, 16308–16313 (2008).
Aldridge, B. B., Saez-Rodriguez, J., Muhlich, J. L., Sorger, P. K. & Lauffenburger, D. A. Fuzzy logic analysis of kinase pathway crosstalk in TNF/EGF/insulin-induced signaling. PLoS Comput. Biol. 5, e1000340 (2009).
Acknowledgements
We thank J. Roose, H. Eisen and A. Weiss for comments on the manuscript. A.K.C. is grateful to M. Davis, A. Shaw and A. Weiss for continuing collaborations and lessons in T cell signalling. Financial support was provided by the US National Institutes of Health (NIH) Director's Pioneer Award and 1PO1/AI071195/01.
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Glossary
- Hysteresis
-
A biological system's memory of its recent history. For example, a cell may respond to a certain stimulus weakly if it is subject to stimulation for the first time, but it may respond strongly to the same stimulus if it has recently been robustly stimulated.
- MicroRNA
-
Small (∼21–23 nucleotides in length), single-stranded RNA molecules that regulate the expression of genes by binding to the 3′ untranslated regions of homologous target mRNAs.
- Immunological synapse
-
A large junctional structure that is formed at the cell surface between a T cell that is interacting with an antigen-presenting cell. Important molecules involved in T cell activation, including the T cell receptor, numerous signal-transduction molecules and molecular adaptors, accumulate in an orderly manner at this site.
- Kinetic proofreading
-
A model of T cell activation in which a series of sequential modifications (such as phosphorylation) of the TCR needs to be completed for the triggering of downstream signalling events. TCR modifications are reversed if the ligand and TCR dissociate prior to reaching the terminal state of modification. The model, therefore, suggests that there is a threshold time that a TCR needs to remain bound to a peptide–MHC complex for T cell activation.
- Anergy
-
A state of unresponsiveness that is sometimes observed in T and B cells that are chronically stimulated or are stimulated through the antigen receptor in the absence of co-stimulatory signals.
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Chakraborty, A., Das, J. Pairing computation with experimentation: a powerful coupling for understanding T cell signalling. Nat Rev Immunol 10, 59–71 (2010). https://doi.org/10.1038/nri2688
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DOI: https://doi.org/10.1038/nri2688
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