Skip to main content
NCBI home page
Proceedings of the Royal Society B: Biological Sciences logoLink to Proceedings of the Royal Society B: Biological Sciences
. 1998 Mar 22;265(1395):529–535. doi: 10.1098/rspb.1998.0327

Dynamics of T-cell antagonism: enhanced viral diversity and survival.

N J Burroughs 1, D A Rand 1
PMCID: PMC1688914  PMID: 9569671

Abstract

In rapidly evolving viruses the detection of virally infected cells can possibly be subverted by the production of altered peptides. There are peptides with single amino acid changes that can dramatically change T-cell responses, e.g. a loss of cytotoxic activity. They are still recognized by the T cell, but the signals required for effector function are only partially delivered. Thus, altered peptide presenting cells can act as decoy targets for specific immune responses. The existence of altered peptides in vivo has been demonstrated in hepatitis B and HIV. Using a mathematical model we address the question of how these altered peptides can affect the virus-immune system dynamics, and demonstrate that virus survival is enhanced. If the mutation rate of the virus is sufficient, one observes complex dynamics in which the antagonism acts so as to maintain the viral diversity, possibly leading to the development of a mutually antagonistic network or a continual turnover of escape mutants. In either case the pathogen is able to outrun the immune system. Indeed, sometimes the enhancement is so great that a virus that would normally be cleared by the immune system is able to outrun it.

Full Text

The Full Text of this article is available as a PDF (174.2 KB).

Selected References

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

  1. Berke G. The binding and lysis of target cells by cytotoxic lymphocytes: molecular and cellular aspects. Annu Rev Immunol. 1994;12:735–773. doi: 10.1146/annurev.iy.12.040194.003511. [DOI] [PubMed] [Google Scholar]
  2. Bertoletti A., Sette A., Chisari F. V., Penna A., Levrero M., De Carli M., Fiaccadori F., Ferrari C. Natural variants of cytotoxic epitopes are T-cell receptor antagonists for antiviral cytotoxic T cells. Nature. 1994 Jun 2;369(6479):407–410. doi: 10.1038/369407a0. [DOI] [PubMed] [Google Scholar]
  3. Brodsky F. M., Guagliardi L. E. The cell biology of antigen processing and presentation. Annu Rev Immunol. 1991;9:707–744. doi: 10.1146/annurev.iy.09.040191.003423. [DOI] [PubMed] [Google Scholar]
  4. Cohen J. J., Duke R. C., Fadok V. A., Sellins K. S. Apoptosis and programmed cell death in immunity. Annu Rev Immunol. 1992;10:267–293. doi: 10.1146/annurev.iy.10.040192.001411. [DOI] [PubMed] [Google Scholar]
  5. De Boer R. J., Perelson A. S. T cell repertoires and competitive exclusion. J Theor Biol. 1994 Aug 21;169(4):375–390. doi: 10.1006/jtbi.1994.1160. [DOI] [PubMed] [Google Scholar]
  6. Franco A., Southwood S., Arrhenius T., Kuchroo V. K., Grey H. M., Sette A., Ishioka G. Y. T cell receptor antagonist peptides are highly effective inhibitors of experimental allergic encephalomyelitis. Eur J Immunol. 1994 Apr;24(4):940–946. doi: 10.1002/eji.1830240424. [DOI] [PubMed] [Google Scholar]
  7. Jameson S. C., Bevan M. J. T cell receptor antagonists and partial agonists. Immunity. 1995 Jan;2(1):1–11. doi: 10.1016/1074-7613(95)90074-8. [DOI] [PubMed] [Google Scholar]
  8. Jameson S. C., Carbone F. R., Bevan M. J. Clone-specific T cell receptor antagonists of major histocompatibility complex class I-restricted cytotoxic T cells. J Exp Med. 1993 Jun 1;177(6):1541–1550. doi: 10.1084/jem.177.6.1541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Klenerman P., Meier U. C., Phillips R. E., McMichael A. J. The effects of natural altered peptide ligands on the whole blood cytotoxic T lymphocyte response to human immunodeficiency virus. Eur J Immunol. 1995 Jul;25(7):1927–1931. doi: 10.1002/eji.1830250720. [DOI] [PubMed] [Google Scholar]
  10. Klenerman P., Rowland-Jones S., McAdam S., Edwards J., Daenke S., Lalloo D., Köppe B., Rosenberg W., Boyd D., Edwards A. Cytotoxic T-cell activity antagonized by naturally occurring HIV-1 Gag variants. Nature. 1994 Jun 2;369(6479):403–407. doi: 10.1038/369403a0. [DOI] [PubMed] [Google Scholar]
  11. Lombardi G., Sidhu S., Batchelor R., Lechler R. Anergic T cells as suppressor cells in vitro. Science. 1994 Jun 10;264(5165):1587–1589. doi: 10.1126/science.8202711. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. Nowak M. A., Bonhoeffer S., Hill A. M., Boehme R., Thomas H. C., McDade H. Viral dynamics in hepatitis B virus infection. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4398–4402. doi: 10.1073/pnas.93.9.4398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Nowak M. A., May R. M. Coexistence and competition in HIV infections. J Theor Biol. 1992 Dec 7;159(3):329–342. doi: 10.1016/s0022-5193(05)80728-3. [DOI] [PubMed] [Google Scholar]
  15. Nowak M. A., May R. M., Sigmund K. Immune responses against multiple epitopes. J Theor Biol. 1995 Aug 7;175(3):325–353. doi: 10.1006/jtbi.1995.0146. [DOI] [PubMed] [Google Scholar]
  16. O'Rourke A. M., Mescher M. F. Cytotoxic T-lymphocyte activation involves a cascade of signalling and adhesion events. Nature. 1992 Jul 16;358(6383):253–255. doi: 10.1038/358253a0. [DOI] [PubMed] [Google Scholar]
  17. Podack E. R., Kupfer A. T-cell effector functions: mechanisms for delivery of cytotoxicity and help. Annu Rev Cell Biol. 1991;7:479–504. doi: 10.1146/annurev.cb.07.110191.002403. [DOI] [PubMed] [Google Scholar]
  18. Razvi E. S., Welsh R. M., McFarland H. I. In vivo state of antiviral CTL precursors. Characterization of a cycling cell population containing CTL precursors in immune mice. J Immunol. 1995 Jan 15;154(2):620–632. [PubMed] [Google Scholar]
  19. Ruppert J., Alexander J., Snoke K., Coggeshall M., Herbert E., McKenzie D., Grey H. M., Sette A. Effect of T-cell receptor antagonism on interaction between T cells and antigen-presenting cells and on T-cell signaling events. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2671–2675. doi: 10.1073/pnas.90.7.2671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Sette A., Alexander J., Ruppert J., Snoke K., Franco A., Ishioka G., Grey H. M. Antigen analogs/MHC complexes as specific T cell receptor antagonists. Annu Rev Immunol. 1994;12:413–431. doi: 10.1146/annurev.iy.12.040194.002213. [DOI] [PubMed] [Google Scholar]
  21. Sewell A. K., Harcourt G. C., Goulder P. J., Price D. A., Phillips R. E. Antagonism of cytotoxic T lymphocyte-mediated lysis by natural HIV-1 altered peptide ligands requires simultaneous presentation of agonist and antagonist peptides. Eur J Immunol. 1997 Sep;27(9):2323–2329. doi: 10.1002/eji.1830270929. [DOI] [PubMed] [Google Scholar]
  22. Sloan-Lancaster J., Allen P. M. Altered peptide ligand-induced partial T cell activation: molecular mechanisms and role in T cell biology. Annu Rev Immunol. 1996;14:1–27. doi: 10.1146/annurev.immunol.14.1.1. [DOI] [PubMed] [Google Scholar]
  23. Spriggs M. K. One step ahead of the game: viral immunomodulatory molecules. Annu Rev Immunol. 1996;14:101–130. doi: 10.1146/annurev.immunol.14.1.101. [DOI] [PubMed] [Google Scholar]
  24. Valitutti S., Lanzavecchia A. Serial triggering of TCRs: a basis for the sensitivity and specificity of antigen recognition. Immunol Today. 1997 Jun;18(6):299–304. [PubMed] [Google Scholar]
  25. Valitutti S., Müller S., Cella M., Padovan E., Lanzavecchia A. Serial triggering of many T-cell receptors by a few peptide-MHC complexes. Nature. 1995 May 11;375(6527):148–151. doi: 10.1038/375148a0. [DOI] [PubMed] [Google Scholar]
  26. Valitutti S., Müller S., Dessing M., Lanzavecchia A. Different responses are elicited in cytotoxic T lymphocytes by different levels of T cell receptor occupancy. J Exp Med. 1996 Apr 1;183(4):1917–1921. doi: 10.1084/jem.183.4.1917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Yannelli J. R., Sullivan J. A., Mandell G. L., Engelhard V. H. Reorientation and fusion of cytotoxic T lymphocyte granules after interaction with target cells as determined by high resolution cinemicrography. J Immunol. 1986 Jan;136(2):377–382. [PubMed] [Google Scholar]

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

RESOURCES