Skip to main content
Proceedings of the Royal Society B: Biological Sciences logoLink to Proceedings of the Royal Society B: Biological Sciences
. 2004 May 7;271(1542):931–939. doi: 10.1098/rspb.2003.2587

Feedback control of T-cell receptor activation.

Cliburn Chan 1, Jaroslav Stark 1, Andrew J T George 1
PMCID: PMC1691681  PMID: 15255048

Abstract

The specificity and sensitivity of T-cell recognition is vital to the immune response. Ligand engagement with the T-cell receptor (TCR) results in the activation of a complex sequence of signalling events, both on the cell membrane and intracellularly. Feedback is an integral part of these signalling pathways, yet is often ignored in standard accounts of T-cell signalling. Here we show, using a mathematical model, that these feedback loops can explain the ability of the TCR to discriminate between ligands with high specificity and sensitivity, as well as provide a mechanism for sustained signalling. The model also explains the recent counter-intuitive observation that endogenous 'null' ligands can significantly enhance T-cell signalling. Finally, the model may provide an archetype for receptor switching based on kinase-phosphatase switches, and thus be of interest to the wider signalling community.

Full Text

The Full Text of this article is available as a PDF (173.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abraham N., Miceli M. C., Parnes J. R., Veillette A. Enhancement of T-cell responsiveness by the lymphocyte-specific tyrosine protein kinase p56lck. Nature. 1991 Mar 7;350(6313):62–66. doi: 10.1038/350062a0. [DOI] [PubMed] [Google Scholar]
  2. Anton van der Merwe P., Davis S. J., Shaw A. S., Dustin M. L. Cytoskeletal polarization and redistribution of cell-surface molecules during T cell antigen recognition. Semin Immunol. 2000 Feb;12(1):5–21. doi: 10.1006/smim.2000.0203. [DOI] [PubMed] [Google Scholar]
  3. Ardouin L., Boyer C., Gillet A., Trucy J., Bernard A. M., Nunes J., Delon J., Trautmann A., He H. T., Malissen B. Crippling of CD3-zeta ITAMs does not impair T cell receptor signaling. Immunity. 1999 Apr;10(4):409–420. doi: 10.1016/s1074-7613(00)80041-2. [DOI] [PubMed] [Google Scholar]
  4. Bonnard M., Maroun C. R., Julius M. Physical association of CD4 and CD45 in primary, resting CD4+ T cells. Cell Immunol. 1997 Jan 10;175(1):1–11. doi: 10.1006/cimm.1996.1044. [DOI] [PubMed] [Google Scholar]
  5. Bunnell Stephen C., Hong David I., Kardon Julia R., Yamazaki Tetsuo, McGlade C. Jane, Barr Valarie A., Samelson Lawrence E. T cell receptor ligation induces the formation of dynamically regulated signaling assemblies. J Cell Biol. 2002 Sep 30;158(7):1263–1275. doi: 10.1083/jcb.200203043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Burack W. Richard, Cheng Alec M., Shaw Andrey S. Scaffolds, adaptors and linkers of TCR signaling: theory and practice. Curr Opin Immunol. 2002 Jun;14(3):312–316. doi: 10.1016/s0952-7915(02)00347-3. [DOI] [PubMed] [Google Scholar]
  7. Cahir McFarland E. D., Hurley T. R., Pingel J. T., Sefton B. M., Shaw A., Thomas M. L. Correlation between Src family member regulation by the protein-tyrosine-phosphatase CD45 and transmembrane signaling through the T-cell receptor. Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1402–1406. doi: 10.1073/pnas.90.4.1402. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chan C., George A. J., Stark J. Cooperative enhancement of specificity in a lattice of T cell receptors. Proc Natl Acad Sci U S A. 2001 May 8;98(10):5758–5763. doi: 10.1073/pnas.101113698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. D'Oro U., Sakaguchi K., Appella E., Ashwell J. D. Mutational analysis of Lck in CD45-negative T cells: dominant role of tyrosine 394 phosphorylation in kinase activity. Mol Cell Biol. 1996 Sep;16(9):4996–5003. doi: 10.1128/mcb.16.9.4996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Davis M. M., Boniface J. J., Reich Z., Lyons D., Hampl J., Arden B., Chien Y. Ligand recognition by alpha beta T cell receptors. Annu Rev Immunol. 1998;16:523–544. doi: 10.1146/annurev.immunol.16.1.523. [DOI] [PubMed] [Google Scholar]
  11. Ehrlich Lauren I. Richie, Ebert Peter J. R., Krummel Matthew F., Weiss Arthur, Davis Mark M. Dynamics of p56lck translocation to the T cell immunological synapse following agonist and antagonist stimulation. Immunity. 2002 Dec;17(6):809–822. doi: 10.1016/s1074-7613(02)00481-8. [DOI] [PubMed] [Google Scholar]
  12. Ferrell James E., Jr Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability. Curr Opin Cell Biol. 2002 Apr;14(2):140–148. doi: 10.1016/s0955-0674(02)00314-9. [DOI] [PubMed] [Google Scholar]
  13. Germain R. N., Stefanová I. The dynamics of T cell receptor signaling: complex orchestration and the key roles of tempo and cooperation. Annu Rev Immunol. 1999;17:467–522. doi: 10.1146/annurev.immunol.17.1.467. [DOI] [PubMed] [Google Scholar]
  14. Germain R. N. The art of the probable: system control in the adaptive immune system. Science. 2001 Jul 13;293(5528):240–245. doi: 10.1126/science.1062946. [DOI] [PubMed] [Google Scholar]
  15. Gil Diana, Schamel Wolfgang W. A., Montoya María, Sánchez-Madrid Francisco, Alarcón Balbino. Recruitment of Nck by CD3 epsilon reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. Cell. 2002 Jun 28;109(7):901–912. doi: 10.1016/s0092-8674(02)00799-7. [DOI] [PubMed] [Google Scholar]
  16. Holdorf Amy D., Lee Kyeong-Hee, Burack W. Richard, Allen Paul M., Shaw Andrey S. Regulation of Lck activity by CD4 and CD28 in the immunological synapse. Nat Immunol. 2002 Feb 4;3(3):259–264. doi: 10.1038/ni761. [DOI] [PubMed] [Google Scholar]
  17. Iezzi G., Karjalainen K., Lanzavecchia A. The duration of antigenic stimulation determines the fate of naive and effector T cells. Immunity. 1998 Jan;8(1):89–95. doi: 10.1016/s1074-7613(00)80461-6. [DOI] [PubMed] [Google Scholar]
  18. Kaufman M., Andris F., Leo O. A model for antigen-induced T cell unresponsiveness based on autophosphorylative protein tyrosine kinase activity. Int Immunol. 1996 Apr;8(4):613–624. doi: 10.1093/intimm/8.4.613. [DOI] [PubMed] [Google Scholar]
  19. 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. 1998 Dec;9(6):817–826. doi: 10.1016/s1074-7613(00)80647-0. [DOI] [PubMed] [Google Scholar]
  20. König Rolf. Interactions between MHC molecules and co-receptors of the TCR. Curr Opin Immunol. 2002 Feb;14(1):75–83. doi: 10.1016/s0952-7915(01)00300-4. [DOI] [PubMed] [Google Scholar]
  21. Lee Kyeong-Hee, Holdorf Amy D., Dustin Michael L., Chan Andrew C., Allen Paul M., Shaw Andrey S. T cell receptor signaling precedes immunological synapse formation. Science. 2002 Feb 22;295(5559):1539–1542. doi: 10.1126/science.1067710. [DOI] [PubMed] [Google Scholar]
  22. Lee Sung-Joo E., Hori Yuko, Groves Jay T., Dustin Michael L., Chakraborty Arup K. Correlation of a dynamic model for immunological synapse formation with effector functions: two pathways to synapse formation. Trends Immunol. 2002 Oct;23(10):492–499. doi: 10.1016/s1471-4906(02)02285-8. [DOI] [PubMed] [Google Scholar]
  23. Madrenas J., Wange R. L., Wang J. L., Isakov N., Samelson L. E., Germain R. N. Zeta phosphorylation without ZAP-70 activation induced by TCR antagonists or partial agonists. Science. 1995 Jan 27;267(5197):515–518. doi: 10.1126/science.7824949. [DOI] [PubMed] [Google Scholar]
  24. McKeithan T. W. Kinetic proofreading in T-cell receptor signal transduction. Proc Natl Acad Sci U S A. 1995 May 23;92(11):5042–5046. doi: 10.1073/pnas.92.11.5042. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Molina T. J., Kishihara K., Siderovski D. P., van Ewijk W., Narendran A., Timms E., Wakeham A., Paige C. J., Hartmann K. U., Veillette A. Profound block in thymocyte development in mice lacking p56lck. Nature. 1992 May 14;357(6374):161–164. doi: 10.1038/357161a0. [DOI] [PubMed] [Google Scholar]
  26. Ostergaard H. L., Shackelford D. A., Hurley T. R., Johnson P., Hyman R., Sefton B. M., Trowbridge I. S. Expression of CD45 alters phosphorylation of the lck-encoded tyrosine protein kinase in murine lymphoma T-cell lines. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8959–8963. doi: 10.1073/pnas.86.22.8959. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Ostman A., Böhmer F. D. Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatases. Trends Cell Biol. 2001 Jun;11(6):258–266. doi: 10.1016/s0962-8924(01)01990-0. [DOI] [PubMed] [Google Scholar]
  28. Perez-Villar J. J., Whitney G. S., Bowen M. A., Hewgill D. H., Aruffo A. A., Kanner S. B. CD5 negatively regulates the T-cell antigen receptor signal transduction pathway: involvement of SH2-containing phosphotyrosine phosphatase SHP-1. Mol Cell Biol. 1999 Apr;19(4):2903–2912. doi: 10.1128/mcb.19.4.2903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Plas D. R., Johnson R., Pingel J. T., Matthews R. J., Dalton M., Roy G., Chan A. C., Thomas M. L. Direct regulation of ZAP-70 by SHP-1 in T cell antigen receptor signaling. Science. 1996 May 24;272(5265):1173–1176. doi: 10.1126/science.272.5265.1173. [DOI] [PubMed] [Google Scholar]
  30. Sicheri F., Kuriyan J. Structures of Src-family tyrosine kinases. Curr Opin Struct Biol. 1997 Dec;7(6):777–785. doi: 10.1016/s0959-440x(97)80146-7. [DOI] [PubMed] [Google Scholar]
  31. Sloan-Lancaster J., Presley J., Ellenberg J., Yamazaki T., Lippincott-Schwartz J., Samelson L. E. ZAP-70 association with T cell receptor zeta (TCRzeta): fluorescence imaging of dynamic changes upon cellular stimulation. J Cell Biol. 1998 Nov 2;143(3):613–624. doi: 10.1083/jcb.143.3.613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sloan-Lancaster J., Shaw A. S., Rothbard J. B., Allen P. M. Partial T cell signaling: altered phospho-zeta and lack of zap70 recruitment in APL-induced T cell anergy. Cell. 1994 Dec 2;79(5):913–922. doi: 10.1016/0092-8674(94)90080-9. [DOI] [PubMed] [Google Scholar]
  33. Smith K., Seddon B., Purbhoo M. A., Zamoyska R., Fisher A. G., Merkenschlager M. Sensory adaptation in naive peripheral CD4 T cells. J Exp Med. 2001 Nov 5;194(9):1253–1261. doi: 10.1084/jem.194.9.1253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Stefanová Irena, Hemmer Bernhard, Vergelli Marco, Martin Roland, Biddison William E., Germain Ronald N. TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nat Immunol. 2003 Feb 10;4(3):248–254. doi: 10.1038/ni895. [DOI] [PubMed] [Google Scholar]
  35. Stein P. L., Lee H. M., Rich S., Soriano P. pp59fyn mutant mice display differential signaling in thymocytes and peripheral T cells. Cell. 1992 Sep 4;70(5):741–750. doi: 10.1016/0092-8674(92)90308-y. [DOI] [PubMed] [Google Scholar]
  36. 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. 1996 Jun;4(6):565–571. doi: 10.1016/s1074-7613(00)80483-5. [DOI] [PubMed] [Google Scholar]
  37. Thome M., Duplay P., Guttinger M., Acuto O. Syk and ZAP-70 mediate recruitment of p56lck/CD4 to the activated T cell receptor/CD3/zeta complex. J Exp Med. 1995 Jun 1;181(6):1997–2006. doi: 10.1084/jem.181.6.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Thome M., Germain V., DiSanto J. P., Acuto O. The p56lck SH2 domain mediates recruitment of CD8/p56lck to the activated T cell receptor/CD3/zeta complex. Eur J Immunol. 1996 Sep;26(9):2093–2100. doi: 10.1002/eji.1830260920. [DOI] [PubMed] [Google Scholar]
  39. Wang S., Lehr R., Stevis P., Wang X. M., Trevillyan J., Faltynek C. R. p56lck interactions accelerate autophosphorylation and enhance activity toward exogenous substrates. Arch Biochem Biophys. 1994 Nov 15;315(1):60–67. doi: 10.1006/abbi.1994.1471. [DOI] [PubMed] [Google Scholar]
  40. Wong P., Barton G. M., Forbush K. A., Rudensky A. Y. Dynamic tuning of T cell reactivity by self-peptide-major histocompatibility complex ligands. J Exp Med. 2001 May 21;193(10):1179–1187. doi: 10.1084/jem.193.10.1179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Wülfing Christoph, Sumen Cenk, Sjaastad Michael D., Wu Lawren C., Dustin Michael L., Davis Mark M. Costimulation and endogenous MHC ligands contribute to T cell recognition. Nat Immunol. 2001 Dec 3;3(1):42–47. doi: 10.1038/ni741. [DOI] [PubMed] [Google Scholar]
  42. Yamaguchi H., Hendrickson W. A. Structural basis for activation of human lymphocyte kinase Lck upon tyrosine phosphorylation. Nature. 1996 Dec 5;384(6608):484–489. doi: 10.1038/384484a0. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society

RESOURCES