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Affinity threshold for thymic selection through a T-cell receptor–co-receptor zipper

Nature Reviews Immunology volume 9, pages 207–213 (2009)Cite this article

Abstract

The affinity of the T-cell receptor (TCR) for self antigen is the basis for the selection of a useful (MHC-restricted) and safe (self-tolerant) T-cell repertoire. However, it has been difficult to understand how thymocytes measure ligand affinity and translate this signal into a cellular response. In this Opinion article, we propose a new model that describes how the TCR discriminates between low- and high-affinity ligands, which is based on the duration of TCR–ligand interactions and a 'zipper' mechanism that mediates the interaction of the TCR and co-receptor molecules to initiate negative-selection signalling.

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Figure 1: Thymic selection depends on T-cell receptor affinity for self peptide–MHC complexes.
Figure 2: Apparent affinity determines the dwell time of individual T-cell receptor–co-receptor–peptide–MHC complexes.
Figure 3: Biophysical aspects of ligand dissociation.
Figure 4: Dwell time influences the extent of T-cell receptor–co-receptor zippering and ITAM phosphorylation.

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References

  1. Boehm, T. Quality control in self/nonself discrimination. Cell 125, 845–858 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. von Boehmer, H., Teh, H. S. & Kisielow, P. The thymus selects the useful, neglects the useless and destroys the harmful. Immunol. Today 10, 57–61 (1989).

    Article  CAS  PubMed  Google Scholar 

  3. Starr, T. K., Jameson, S. C. & Hogquist, K. A. Positive and negative selection of T cells. Annu. Rev. Immunol. 21, 139–176 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Werlen, G., Hausmann, B., Naeher, D. & Palmer, E. Signaling life and death in the thymus: timing is everything. Science 299, 1859–1863 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Goldrath, A. W. & Bevan, M. J. Selecting and maintaining a diverse T-cell repertoire. Nature 402, 255–262 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Choi, S. & Schwartz, R. H. Molecular mechanisms for adaptive tolerance and other T cell anergy models. Semin. Immunol. 19, 140–152 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Davey, G. M. et al. Preselection thymocytes are more sensitive to T cell receptor stimulation than mature T cells. J. Exp. Med. 188, 1867–1874 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Schodin, B. A., Tsomides, T. J. & Kranz, D. M. Correlation between the number of T cell receptors required for T cell activation and TCR–ligand affinity. Immunity 5, 137–146 (1996).

    Article  CAS  PubMed  Google Scholar 

  9. Slifka, M. K. & Whitton, J. L. Functional avidity maturation of CD8+ T cells without selection of higher affinity TCR. Nature Immunol. 2, 711–717 (2001).

    Article  CAS  Google Scholar 

  10. Davis, M. M., Chien, Y. H., Gascoigne, N. R. & Hedrick, S. M. A murine T cell receptor gene complex: isolation, structure and rearrangement. Immunol. Rev. 81, 235–258 (1984).

    Article  CAS  PubMed  Google Scholar 

  11. Lo, D., Ron, Y. & Sprent, J. Induction of MHC-restricted specificity and tolerance in the thymus. Immunol. Res. 5, 221–232 (1986).

    Article  CAS  PubMed  Google Scholar 

  12. Lord, G. M., Lechler, R. I. & George, A. J. A kinetic differentiation model for the action of altered TCR ligands. Immunol. Today 20, 33–39 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. George, A. J., Stark, J. & Chan, C. Understanding specificity and sensitivity of T-cell recognition. Trends Immunol. 26, 653–659 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Carreno, L. J., Gonzalez, P. A. & Kalergis, A. M. Modulation of T cell function by TCR/pMHC binding kinetics. Immunobiology 211, 47–64 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Feinerman, O., Germain, R. N. & Altan-Bonnet, G. Quantitative challenges in understanding ligand discrimination by αβ T cells. Mol. Immunol. 45, 619–631 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. de Bont, E. S., Reilly, C. R., Lo, D., Glimcher, L. H. & Laufer, T. M. A minimal level of MHC class II expression is sufficient to abrogate autoreactivity. Int. Immunol. 11, 1295–1306 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Ebert, P. J., Ehrlich, L. I. & Davis, M. M. Low ligand requirement for deletion and lack of synapses in positive selection enforce the gauntlet of thymic T cell maturation. Immunity 29, 734–745 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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).

    Article  CAS  PubMed  Google Scholar 

  19. Alam, S. et al. T-cell-receptor affinity and thymocyte positive selection. Nature 381, 616–620 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Williams, C. B., Engle, D. L., Kersh, G. J., Michael White, J. & Allen, P. M. A kinetic threshold between negative and positive selection based on the longevity of the T cell receptor–ligand complex. J. Exp. Med. 189, 1531–1544 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Love, P. E., Lee, J. & Shores, E. W. Critical relationship between TCR signaling potential and TCR affinity during thymocyte selection. J. Immunol. 165, 3080–3087 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Naeher, D. et al. A constant affinity threshold for T cell tolerance. J. Exp. Med. 204, 2553–2559 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hogquist, K. A. et al. T cell receptor antagonist peptides induce positive selection. Cell 76, 17–27 (1994).

    Article  CAS  PubMed  Google Scholar 

  24. Daniels, M. A. et al. Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature 444, 724–729 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Hogquist, K. A., Jameson, S. C. & Bevan, M. J. Strong agonist ligands for the T cell receptor do not mediate positive selection of functional CD8+ T cells. Immunity 3, 79–86 (1995).

    Article  CAS  PubMed  Google Scholar 

  26. Liu, C. P., Crawford, F., Marrack, P. & Kappler, J. T cell positive selection by a high density, low affinity ligand. Proc. Natl Acad. Sci. USA 95, 4522–4526 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Martinic, M. M., Rocha, B., McCoy, K. D., Hengartner, H. & Zinkernagel, R. M. Role of TCR-restricting MHC density and thymic environment on selection and survival of cells expressing low-affinity T cell receptors. Eur. J. Immunol. 34, 1041–1049 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Nikolic-Zugic, J. & Bevan, M. J. Role of self-peptides in positively selecting the T-cell repertoire. Nature 344, 65–67 (1990).

    Article  CAS  PubMed  Google Scholar 

  29. Watanabe, N., Arase, H., Onodera, M., Ohashi, P. S. & Saito, T. The quantity of TCR signal determines positive selection and lineage commitment of T cells. J. Immunol. 165, 6252–6261 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. van Meerwijk, J. P. et al. Quantitative impact of thymic clonal deletion on the T cell repertoire. J. Exp. Med. 185, 377–383 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Baldwin, K. K., Trenchak, B. P., Altman, J. D. & Davis, M. M. Negative selection of T cells occurs throughout thymic development. J. Immunol. 163, 689–698 (1999).

    CAS  PubMed  Google Scholar 

  32. Viret, C., Sant'Angelo, D. B., He, X., Ramaswamy, H. & Janeway, C. A. Jr. A role for accessibility to self-peptide–self-MHC complexes in intrathymic negative selection. J. Immunol. 166, 4429–4437 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Stefanova, I., Dorfman, J. R. & Germain, R. N. Self-recognition promotes the foreign antigen sensitivity of naive T lymphocytes. Nature 420, 429–434 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Krogsgaard, M. et al. Agonist/endogenous peptide–MHC heterodimers drive T cell activation and sensitivity. Nature 434, 238–243 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. McKeithan, T. W. Kinetic proofreading in T-cell receptor signal transduction. Proc. Natl Acad. Sci. USA 92, 5042–5046 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kersh, G. J., Kersh, E. N., Fremont, D. H. & Allen, P. M. High- and low-potency ligands with similar affinities for the TCR: the importance of kinetics in TCR signaling. Immunity 9, 817–826 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Luescher, I. F., Cerottini, J. C. & Romero, P. Photoaffinity labeling of the T cell receptor on cloned cytotoxic T lymphocytes by covalent photoreactive ligand. J. Biol. Chem. 269, 5574–5582 (1994).

    CAS  PubMed  Google Scholar 

  39. Kalergis, A. M. et al. Efficient T cell activation requires an optimal dwell-time of interaction between the TCR and the pMHC complex. Nature Immunol. 2, 229–234 (2001).

    Article  CAS  Google Scholar 

  40. Savage, P. A. & Davis, M. M. A kinetic window constricts the T cell receptor repertoire in the thymus. Immunity 14, 243–252 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Teague, R. M. et al. Peripheral CD8+ T cell tolerance to self-proteins is regulated proximally at the T cell receptor. Immunity 28, 662–674 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Rabinowitz, J. D., Beeson, C., Lyons, D. S., Davis, M. M. & McConnell, H. M. Kinetic discrimination in T-cell activation. Proc. Natl Acad. Sci. USA 93, 1401–1405 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Reis e Sousa, C., Levine, E. H. & Germain, R. N. Partial signaling by CD8+ T cells in response to antagonist ligands. J. Exp. Med. 184, 149–157 (1996).

    Article  CAS  PubMed  Google Scholar 

  44. 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).

    Article  CAS  PubMed  Google Scholar 

  45. Rachmilewitz, J. & Lanzavecchia, A. A temporal and spatial summation model for T-cell activation: signal integration and antigen decoding. Trends Immunol. 23, 592–595 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Veillette, A., Bookman, M. A., Horak, E. M. & Bolen, J. B. The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck. Cell 55, 301–308 (1988).

    Article  CAS  PubMed  Google Scholar 

  47. Shaw, A. S. et al. The lck tyrosine protein kinase interacts with the cytoplasmic tail of the CD4 glycoprotein through its unique amino-terminal domain. Cell 59, 627–636 (1989).

    Article  CAS  PubMed  Google Scholar 

  48. Wyer, J. R. et al. T cell receptor and coreceptor CD8 αα bind peptide–MHC independently and with distinct kinetics. Immunity 10, 219–225 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. Xiong, Y., Kern, P., Chang, H. & Reinherz, E. T cell receptor binding to a pMHCII ligand is kinetically distinct from and independent of CD4. J. Biol. Chem. 276, 5659–5667 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Holler, P. D. & Kranz, D. M. Quantitative analysis of the contribution of TCR/pepMHC affinity and CD8 to T cell activation. Immunity 18, 255–264 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Luescher, I. F. et al. CD8 modulation of T-cell antigen receptor–ligand interactions on living cytotoxic T lymphocytes. Nature 373, 353–356 (1995).

    Article  CAS  PubMed  Google Scholar 

  52. Mallaun, M. et al. The T cell receptor's α-chain connecting peptide motif promotes close approximation of the CD8 coreceptor allowing efficient signal initiation. J. Immunol. 180, 8211–8221 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Naeher, D., Luescher, I. F. & Palmer, E. A role for the α-chain connecting peptide motif in mediating TCR–CD8 cooperation. J. Immunol. 169, 2964–2970 (2002).

    Article  CAS  PubMed  Google Scholar 

  54. Hamad, A. R. et al. Potent T cell activation with dimeric peptide–major histocompatibility complex class II ligand: the role of CD4 coreceptor. J. Exp. Med. 188, 1633–1640 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Casabo, L. G., Mamalaki, C., Kioussis, D. & Zamoyska, R. T cell activation results in physical modification of the mouse CD8 beta chain. J. Immunol. 152, 397–404 (1994).

    CAS  PubMed  Google Scholar 

  56. Daniels, M. A. et al. CD8 binding to MHC class I molecules is influenced by T cell maturation and glycosylation. Immunity 15, 1051–1061 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Fahmy, T. M., Bieler, J. G., Edidin, M. & Schneck, J. P. Increased TCR avidity after T cell activation: a mechanism for sensing low-density antigen. Immunity 14, 135–143 (2001).

    CAS  PubMed  Google Scholar 

  58. Rudd, P. M. et al. Roles for glycosylation of cell surface receptors involved in cellular immune recognition. J. Mol. Biol. 293, 351–366 (1999).

    Article  CAS  PubMed  Google Scholar 

  59. Gil, D., Schrum, A. G., Daniels, M. A. & Palmer, E. A role for CD8 in the developmental tuning of antigen recognition and CD3 conformational change. J. Immunol. 180, 3900–3909 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Plas, D. R. et al. Direct regulation of ZAP-70 by SHP-1 in T cell antigen receptor signaling. Science 272, 1173–1176 (1996).

    Article  CAS  PubMed  Google Scholar 

  61. Altan-Bonnet, G. & Germain, R. N. Modeling T cell antigen discrimination based on feedback control of digital ERK responses. PLoS Biol. 3, e356 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Li, Q. J. et al. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129, 147–161 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Mingueneau, M. et al. The proline-rich sequence of CD3ɛ controls T cell antigen receptor expression on and signaling potency in preselection CD4+CD8+ thymocytes. Nature Immunol. 9, 522–532 (2008).

    Article  CAS  Google Scholar 

  64. Huse, M. et al. Spatial and temporal dynamics of T cell receptor signaling with a photoactivatable agonist. Immunity 27, 76–88 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Gil, D., Schamel, W. W., Montoya, M., Sanchez- Madrid, F. & Alarcon, B. Recruitment of Nck by CD3ɛ reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. Cell 109, 901–912 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Minguet, S., Swamy, M., Alarcon, B., Luescher, I. F. & Schamel, W. W. Full activation of the T cell receptor requires both clustering and conformational changes at CD3. Immunity 26, 43–54 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Szymczak, A. L. et al. The CD3ɛ proline-rich sequence, and its interaction with Nck, is not required for T cell development and function. J. Immunol. 175, 270–275 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Janeway, C. A. Jr. Ligands for the T-cell receptor: hard times for avidity models. Immunol. Today 16, 223–225 (1995).

    Article  CAS  PubMed  Google Scholar 

  69. Gil, D., Schrum, A. G., Alarcon, B. & Palmer, E. T cell receptor engagement by peptide–MHC ligands induces a conformational change in the CD3 complex of thymocytes. J. Exp. Med. 201, 517–522 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Shores, E. W. et al. Role of the multiple T cell receptor (TCR)-ζ chain signaling motifs in selection of the T cell repertoire. J. Exp. Med. 185, 893–900 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kersh, E. N., Shaw, A. S. & Allen, P. M. Fidelity of T cell activation through multistep T cell receptor-ζ phosphorylation. Science 281, 572–575 (1998).

    Article  CAS  PubMed  Google Scholar 

  72. Madrenas, J. et al. Zeta phosphorylation without ZAP-70 activation induced by TCR antagonists or partial agonists. Science 267, 515–518 (1995).

    Article  CAS  PubMed  Google Scholar 

  73. Xu, H. & Littman, D. R. A kinase-independent function of Lck in potentiating antigen-specific T cell activation. Cell 74, 633–643 (1993).

    Article  CAS  PubMed  Google Scholar 

  74. 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).

    Article  CAS  Google Scholar 

  75. Backstrom, B. T. et al. A motif within the T cell receptor α chain constant region connecting peptide domain controls antigen responsiveness. Immunity 5, 437–447 (1996).

    Article  CAS  PubMed  Google Scholar 

  76. Werlen, G., Hausmann, B. & Palmer, E. A motif in the αβ T-cell receptor controls positive selection by modulating ERK activity. Nature 406, 422–426 (2000).

    Article  CAS  PubMed  Google Scholar 

  77. Doucey, M. A. et al. CD3δ establishes a functional link between the T cell receptor and CD8. J. Biol. Chem. 278, 3257–3264 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Backstrom, B. T., Muller, U., Hausmann, B. & Palmer, E. Positive selection through a motif in the αβ T cell receptor. Science 281, 835–838 (1998).

    Article  CAS  PubMed  Google Scholar 

  79. Demotte, N. et al. Restoring the association of the T cell receptor with CD8 reverses anergy in human tumor-infiltrating lymphocytes. Immunity 28, 414–424 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Kerry, S. E. et al. Interplay between TCR affinity and necessity of coreceptor ligation: high-affinity peptide–MHC/TCR interaction overcomes lack of CD8 engagement. J. Immunol. 171, 4493–4503 (2003).

    Article  CAS  PubMed  Google Scholar 

  81. Weber, K. S., Donermeyer, D. L., Allen, P. M. & Kranz, D. M. Class II-restricted T cell receptor engineered in vitro for higher affinity retains peptide specificity and function. Proc. Natl Acad. Sci. USA 102, 19033–19038 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Fung-Leung, W. P. et al. CD8 is needed for positive selection but differentially required for negative selection of T cells during thymic ontogeny. Eur. J. Immunol. 23, 212–216 (1993).

    Article  CAS  PubMed  Google Scholar 

  83. Goldrath, A. W., Hogquist, K. A. & Bevan, M. J. CD8 lineage commitment in the absence of CD8. Immunity 6, 633–642 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Sebzda, E., Choi, M., Fung-Leung, W. P., Mak, T. W. & Ohashi, P. S. Peptide-induced positive selection of TCR transgenic thymocytes in a coreceptor-independent manner. Immunity 6, 643–653 (1997).

    Article  CAS  PubMed  Google Scholar 

  85. Straus, D. B. & Weiss, A. Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor. Cell 70, 585–593 (1992).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank M. Cohn, G. De Libero, N. Gascoigne, T. Hoefer, S. Jameson, I. Luescher, M. Mallaun, M. Mescher, T. Staehelin, S. Treves and F. Zorzato for comments on the manuscript. We also thank past and present members of the Palmer laboratory for fruitful discussions. The work is supported by grants from the Swiss National Science Foundation, Sybilla (EU FP7), National Institutes of Health, Roche and Novartis.

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  1. Departments of Nephrology and Biomedicine, Ed Palmer and Dieter Naeher are at the Laboratory of Transplantation Immunology, University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland.,

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Palmer, E., Naeher, D. Affinity threshold for thymic selection through a T-cell receptor–co-receptor zipper. Nat Rev Immunol 9, 207–213 (2009). https://doi.org/10.1038/nri2469

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