Antigen potency and maximal efficacy reveal a mechanism of efficient T cell activation

Science Signaling

Volumn 4, Issue 176, 2011, Pages

  Dushek, Omer ^a,b   Aleksic, Milos ^a,e   Wheeler, Richard J ^a   Zhang, Hao ^a   Cordoba, Shaun Paul ^a   Peng, Yan Chun ^c   Chen, Ji Li ^c   Cerundolo, Vincenzo ^c   Dong, Tao ^c   Coombs, Daniel ^d   Van Der Merwe, Philip Anton ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b UNIVERSITY OF OXFORD   (United Kingdom)

^c UNIVERSITY OF OXFORD   (United Kingdom)

^d UNIVERSITY OF BRITISH COLUMBIA   (Canada)

^e Immunocore Limited   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

GAMMA INTERFERON; MAJOR HISTOCOMPATIBILITY ANTIGEN; T LYMPHOCYTE RECEPTOR; ANTIGEN;

ARTICLE; CELL CLONING; CONCENTRATION (PARAMETERS); CONTROLLED STUDY; CYTOKINE RELEASE; CYTOTOXIC T LYMPHOCYTE; MAJOR HISTOCOMPATIBILITY COMPLEX; MATHEMATICAL MODEL; PREDICTION; PRIORITY JOURNAL; SIGNAL TRANSDUCTION; T LYMPHOCYTE ACTIVATION; ADAPTIVE IMMUNITY; ANIMAL; CHEMICAL MODEL; HUMAN; IMMUNOLOGY; LYMPHOCYTE ACTIVATION; MOUSE; T LYMPHOCYTE; THERMODYNAMICS;

ADAPTIVE IMMUNITY; ANIMALS; ANTIGENS; HUMANS; LYMPHOCYTE ACTIVATION; MICE; MODELS, CHEMICAL; T-LYMPHOCYTES; T-LYMPHOCYTES, CYTOTOXIC; THERMODYNAMICS;

EID: 79958213129     PISSN: 19450877     EISSN: 19379145     Source Type: Journal    
DOI: 10.1126/scisignal.2001430     Document Type: Article

References (45)

1. J. E. Smith-Garvin, G. A. Koretzky, M. S. Jordan, T cell activation. Annu. Rev. Immunol. 27, 591-619 (2009).
2. M. Aleksic, O. Dushek, H. Zhang, E. Shenderov, J. L. Chen, V. Cerundolo, D. Coombs, P. A. van der Merwe, Dependence of T cell antigen recognition on T cell receptor-peptide MHC confinement time. Immunity 32, 163-174 (2010).
3. P. S. Andersen, C. Geisler, S. Buus, R. A. Mariuzza, K. Karjalainen, Role of the T cell receptor ligand affinity in T cell activation by bacterial superantigens. J. Biol. Chem. 276, 33452-33457 (2001).
4. P. S. Andersen, C. Menné, R. A. Mariuzza, C. Geisler, K. Karjalainen, A response calculus for immobilized T cell receptor ligands. J. Biol. Chem. 276, 49125-49132 (2001).
5. A. S. Chervin, J. D. Stone, P. D. Holler, A. Bai, J. Chen, H. N. Eisen, D. M. Kranz, The impact of TCR-binding properties and antigen presentation format on T cell responsiveness. J. Immunol. 183, 1166-1178 (2009).
6. D. Coombs, A. M. Kalergis, S. G. Nathenson, C. Wofsy, B. Goldstein, Activated TCRs remain marked for internalization after dissociation from pMHC. Nat. Immunol. 3, 926-931 (2002).
7. P. A. González, L. J. Carreño, D. Coombs, J. E. Mora, E. Palmieri, B. Goldstein, S. G. Nathenson, A. M. Kalergis, 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. U.S.A. 102, 4824-4829 (2005).
8. C. C. Govern, M. K. Paczosa, A. K. Chakraborty, E. S. Huseby, Fast on-rates allow short dwell time ligands to activate T cells. Proc. Natl. Acad. Sci. U.S.A. 107, 8724-8729 (2010).
9. P. D. Holler, D. M. Kranz, Quantitative analysis of the contribution of TCR/pepMHC affinity and CD8 to T cell activation. Immunity 18, 255-264 (2003).
10. J. Huang, V. I. Zarnitsyna, B. Liu, L. J. Edwards, N. Jiang, B. D. Evavold, C. Zhu, The kinetics of two-dimensional TCR and pMHC interactions determine T-cell responsiveness. Nature 464, 932-936 (2010).
11. + CTL clones is determined by the frequency of serial TCR engagement. J. Immunol. 161, 553-562 (1998).
12. A. M. Kalergis, N. Boucheron, M. A. Doucey, E. Palmieri, E. C. Goyarts, Z. Vegh, I. F. Luescher, S. G. Nathenson, Efficient T cell activation requires an optimal dwell-time of interaction between the TCR and the pMHC complex. Nat. Immunol. 2, 229-234 (2001).
13. M. Krogsgaard, N. Prado, E. J. Adams, X. L. He, D. C. Chow, D. B. Wilson, K. C. Garcia, M. M. Davis, Evidence that structural rearrangements and/or flexibility during TCR binding can contribute to T cell activation. Mol. Cell 12, 1367-1378 (2003).
14. R. H. McMahan, J. A. McWilliams, K. R. Jordan, S. W. Dow, D. B. Wilson, J. E. Slansky, Relating TCR-peptide-MHC affinity to immunogenicity for the design of tumor vaccines. J. Clin. Invest. 116, 2543-2551 (2006).
15. + T cell activation is governed by TCR-peptide/MHC affinity, not dissociation rate. J. Immunol. 179, 2952-2960 (2007).
16. S. Valitutti, S. Müller, M. Cella, E. Padovan, A. Lanzavecchia, Serial triggering of many T-cell receptors by a few peptide-MHC complexes. Nature 375, 148-151 (1995).
17. T. W. McKeithan, Kinetic proofreading in T-cell receptor signal transduction. Proc. Natl. Acad. Sci. U.S.A. 92, 5042-5046 (1995).
18. J. D. Rabinowitz, C. Beeson, C. Wülfing, K. Tate, P. M. Allen, M. M. Davis, H. M. McConnell, Altered T cell receptor ligands trigger a subset of early T cell signals. Immunity 5, 125-135 (1996).
19. J. M. Boulter, B. K. Jakobsen, Stable, soluble, high-affinity, engineered T cell receptors: Novel antibody-like proteins for specific targeting of peptide antigens. Clin. Exp. Immunol. 142, 454-460 (2005).
20. Y. Li, R. Moysey, P. E. Molloy, A. L. Vuidepot, T. Mahon, E. Baston, S. Dunn, N. Liddy, J. Jacob, B. K. Jakobsen, J. M. Boulter, Directed evolution of human T-cell receptors with picomolar affinities by phage display. Nat. Biotechnol. 23, 349-354 (2005).
21. P. E. Molloy, A. K. Sewell, B. K. Jakobsen, Soluble T cell receptors: Novel immunotherapies. Curr. Opin. Pharmacol. 5, 438-443 (2005).
22. E. Corse, R. A. Gottschalk, M. Krogsgaard, J. P. Allison, Attenuated T cell responses to a high-potency ligand in vivo. PLoS Biol. 8, e1000481 (2010).
23. P. F. Robbins, Y. F. Li, M. El-Gamil, Y. Zhao, J. A. Wargo, Z. Zheng, H. Xu, R. A. Morgan, S. A. Feldman, L. A. Johnson, A. D. Bennett, S. M. Dunn, T. M. Mahon, B. K. Jakobsen, S. A. Rosenberg, Single and dual amino acid substitutions in TCR CDRs can enhance antigen-specific T cell functions. J. Immunol. 180, 6116-6131 (2008).
24. + T cells with the ability to recognize and kill tumor cell lines. J. Immunol. 179, 5845-5854 (2007).
25. D. Colquhoun, Binding, gating, affinity and efficacy: The interpretation of structure-activity relationships for agonists and of the effects of mutating receptors. Br. J. Pharmacol. 125, 924-947 (1998).
26. J. M. Weiss, P. H. Morgan, M. W. Lutz, T. P. Kenakin, The cubic ternary complex receptoroccupancy model. III. Resurrecting efficacy. J. Theor. Biol. 181, 381-397 (1996).
27. Z. Borovsky, G. Mishan-Eisenberg, E. Yaniv, J. Rachmilewitz, Serial triggering of T cell receptors results in incremental accumulation of signaling intermediates. J. Biol. Chem. 277, 21529-21536 (2002).
28. J. K. Lee, G. Stewart-Jones, T. Dong, K. Harlos, K. Di Gleria, L. Dorrell, D. C. Douek, P. A. van der Merwe, E. Y. Jones, A. J. McMichael, T cell cross-reactivity and conformational changes during TCR engagement. J. Exp. Med. 200, 1455-1466 (2004).
29. S. Qi, M. Krogsgaard, M. M. Davis, A. K. Chakraborty, Molecular flexibility can influence the stimulatory ability of receptor-ligand interactions at cell-cell junctions. Proc. Natl. Acad. Sci. U.S.A. 103, 4416-4421 (2006).
30. O. Dushek, R. Das, D. Coombs, A role for rebinding in rapid and reliable T cell responses to antigen. PLoS Comput. Biol. 5, e1000578 (2009).
31. G. I. Bell, Models for the specific adhesion of cells to cells. Science 200, 618-627 (1978).
32. A. Pierres, A. M. Benoliel, P. Bongrand, Studying molecular interactions at the single bond level with a laminar flow chamber. Cell. Mol. Bioeng. 1, 247-262 (2008).
33. R. A. Gottschalk, E. Corse, J. P. Allison, TCR ligand density and affinity determine peripheral induction of Foxp3 in vivo. J. Exp. Med. 207, 1701-1711 (2010).
34. A. Varela-Rohena, P. E. Molloy, S. M. Dunn, Y. Li, M. M. Suhoski, R. G. Carroll, A. Milicic, T. Mahon, D. H. Sutton, B. Laugel, R. Moysey, B. J. Cameron, A. Vuidepot, M. A. Purbhoo, D. K. Cole, R. E. Phillips, C. H. June, B. K. Jakobsen, A. K. Sewell, J. L. Riley, Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor. Nat. Med. 14, 1390-1395 (2008).
35. J. B. Huppa, M. Axmann, M. A. Mortelmaier, B. F. Lillemeier, E. W. Newell, M. Brameshuber, L. O. Klein, G. J. Schütz, M. M. Davis, TCR-peptide-MHC interactions in situ show accelerated kinetics and increased affinity. Nature 463, 963-967 (2010).
36. P. A. van der Merwe, O. Dushek, Mechanisms for T cell receptor triggering. Nat. Rev. Immunol. 11, 47-55 (2011).
37. G. Altan-Bonnet, R. N. Germain, Modeling T cell antigen discrimination based on feedback control of digital ERK responses. PLoS Biol. 3, e356 (2005).
38. J. Das, M. Ho, J. Zikherman, C. Govern, M. Yang, A. Weiss, A. K. Chakraborty, J. P. Roose, Digital signaling and hysteresis characterize ras activation in lymphoid cells. Cell 136, 337-351 (2009).
39. + T cells. J. Exp. Med. 186, 757-766 (1997).
40. E. Corse, R. A. Gottschalk, J. P. Allison, Strength of TCR-peptide/MHC interactions and in vivo T cell responses. J. Immunol. 186, 5039-5045 (2011).
41. J. E. Slansky, K. R. Jordan, The Goldilocks model for TCR - too much attraction might not be best for vaccine design. PLoS Biol. 8, e1000482 (2010).
42. A. J. Clark, The reaction between acetyl choline and muscle cells. J. Physiol. 61, 530-546 (1926).
43. W. D. Paton, A theory of drug action based on rate of drug-receptor combination. Proc. R. Soc. Lond. B Biol. Sci. 154, 21-69 (1961).
44. R. A. Copeland, D. L. Pompliano, T. D. Meek, Drug-target residence time and its implications for lead optimization. Nat. Rev. Drug Discov. 5, 730-739 (2006).
45. Acknowledgments: We thank M. Bridge for protein expression and V. Shahrezaei for discussions. We thank the anonymous reviewers for their constructive comments. Funding: Supported by the Medical Research Council (UK), the National Science and Engineering Research Council (Canada), the Mathematics of Information Technology and Complex Systems National Centre of Excellence (Canada), the Biotechnology and Biological Sciences Research Council (UK) through the I2M network, a Wellcome Trust Ph.D. studentship (to R.J.W.), and the Royal Society through a Newton Fellowship (to O.D.). Author contributions: M.A., O.D., S.-P.C., and R.J.W. performed the experiments; H.Z., Y.-C.P., J.-L.C., V.C., and T.D. generated the reagents; O.D. performed the mathematical modeling; and O.D., M.A., D.C., and P.A.v.d.M. designed the research, analyzed the data, and wrote the paper. Competing interests: The authors declare that they have no competing interests.