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. 1992 May 15;89(10):4643–4647. doi: 10.1073/pnas.89.10.4643

How cytotoxic T cells manage to discriminate nonself from self at the nonapeptide level.

S Ohno 1
PMCID: PMC49139  PMID: 1374910

Abstract

Class I major histocompatibility complex (MHC) antigens are confronted with an apparently insurmountable dilemma. Each should show a binding preference to a common enough variety of nonapeptides, so that one relevant nonapeptide can be found in at least every other viral protein to provoke a cytotoxic T-cell response. By so doing, however, the chance of that viral T epitope being self is greatly increased. Examination of human and viral nonapeptides preferred by HLA-B27 led to the following conclusions. (i) In normal cells, peptide fragments originating from 5000 or more diverse proteins vie for a finite number of class I MHC sites. Consequently, only those nonapeptides having the optimal binding affinity to a given class I MHC antigen can gain access to the plasma membrane. (ii) Tolerance is rendered only to those host nonapeptides with the optimal binding affinity. (iii) Because of the above noted tolerance, viral nonapeptides with the optimal binding affinity are invariably ignored. (iv) Viral T epitopes actually chosen are always second-echelon nonapeptides that are endowed with slightly less than the optimal binding affinity to a given class I MHC antigen. (v) Since such second-echelon nonapeptides would not gain access to the plasma membrane in normal cells, the issue of self or nonself is rendered irrelevant by this choice. (vi) Since viral T epitopes are of this type, cytotoxic T-cell responses against infected cells are expected to be effective only when a few viral proteins are made in large amounts at the expense of host proteins.

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Selected References

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

  1. Allard W. J., Sigal I. S., Dixon R. A. Sequence of the gene encoding the human M1 muscarinic acetylcholine receptor. Nucleic Acids Res. 1987 Dec 23;15(24):10604–10604. doi: 10.1093/nar/15.24.10604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Christinck E. R., Luscher M. A., Barber B. H., Williams D. B. Peptide binding to class I MHC on living cells and quantitation of complexes required for CTL lysis. Nature. 1991 Jul 4;352(6330):67–70. doi: 10.1038/352067a0. [DOI] [PubMed] [Google Scholar]
  3. Falk K., Rötzschke O., Stevanović S., Jung G., Rammensee H. G. Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature. 1991 May 23;351(6324):290–296. doi: 10.1038/351290a0. [DOI] [PubMed] [Google Scholar]
  4. Gotch F., Rothbard J., Howland K., Townsend A., McMichael A. Cytotoxic T lymphocytes recognize a fragment of influenza virus matrix protein in association with HLA-A2. 1987 Apr 30-May 6Nature. 326(6116):881–882. doi: 10.1038/326881a0. [DOI] [PubMed] [Google Scholar]
  5. Greene G. L., Gilna P., Waterfield M., Baker A., Hort Y., Shine J. Sequence and expression of human estrogen receptor complementary DNA. Science. 1986 Mar 7;231(4742):1150–1154. doi: 10.1126/science.3753802. [DOI] [PubMed] [Google Scholar]
  6. Huet S., Nixon D. F., Rothbard J. B., Townsend A., Ellis S. A., McMichael A. J. Structural homologies between two HLA B27-restricted peptides suggest residues important for interaction with HLA B27. Int Immunol. 1990;2(4):311–316. doi: 10.1093/intimm/2.4.311. [DOI] [PubMed] [Google Scholar]
  7. Jardetzky T. S., Lane W. S., Robinson R. A., Madden D. R., Wiley D. C. Identification of self peptides bound to purified HLA-B27. Nature. 1991 Sep 26;353(6342):326–329. doi: 10.1038/353326a0. [DOI] [PubMed] [Google Scholar]
  8. Madden D. R., Gorga J. C., Strominger J. L., Wiley D. C. The structure of HLA-B27 reveals nonamer self-peptides bound in an extended conformation. Nature. 1991 Sep 26;353(6342):321–325. doi: 10.1038/353321a0. [DOI] [PubMed] [Google Scholar]
  9. Meyerhans A., Dadaglio G., Vartanian J. P., Langlade-Demoyen P., Frank R., Asjö B., Plata F., Wain-Hobson S. In vivo persistence of a HIV-1-encoded HLA-B27-restricted cytotoxic T lymphocyte epitope despite specific in vitro reactivity. Eur J Immunol. 1991 Oct;21(10):2637–2640. doi: 10.1002/eji.1830211051. [DOI] [PubMed] [Google Scholar]
  10. Michelson A. M., Markham A. F., Orkin S. H. Isolation and DNA sequence of a full-length cDNA clone for human X chromosome-encoded phosphoglycerate kinase. Proc Natl Acad Sci U S A. 1983 Jan;80(2):472–476. doi: 10.1073/pnas.80.2.472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Minghetti P. P., Ruffner D. E., Kuang W. J., Dennison O. E., Hawkins J. W., Beattie W. G., Dugaiczyk A. Molecular structure of the human albumin gene is revealed by nucleotide sequence within q11-22 of chromosome 4. J Biol Chem. 1986 May 25;261(15):6747–6757. [PubMed] [Google Scholar]
  12. Nixon D. F., Townsend A. R., Elvin J. G., Rizza C. R., Gallwey J., McMichael A. J. HIV-1 gag-specific cytotoxic T lymphocytes defined with recombinant vaccinia virus and synthetic peptides. Nature. 1988 Dec 1;336(6198):484–487. doi: 10.1038/336484a0. [DOI] [PubMed] [Google Scholar]
  13. Ohno S. Many peptide fragments of alien antigens are homologous with host proteins, thus canalizing T-cell responses. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3065–3068. doi: 10.1073/pnas.88.8.3065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ohno S. To be or not to be a responder in T-cell responses: ubiquitous oligopeptides in all proteins. Immunogenetics. 1991;34(4):215–221. doi: 10.1007/BF00215255. [DOI] [PubMed] [Google Scholar]
  15. Rapp G., Klaudiny J., Hagendorff G., Luck M. R., Scheit K. H. Complete sequence of the coding region of human elongation factor 2 (EF-2) by enzymatic amplification of cDNA from human ovarian granulosa cells. Biol Chem Hoppe Seyler. 1989 Oct;370(10):1071–1075. doi: 10.1515/bchm3.1989.370.2.1071. [DOI] [PubMed] [Google Scholar]
  16. Ratner L., Haseltine W., Patarca R., Livak K. J., Starcich B., Josephs S. F., Doran E. R., Rafalski J. A., Whitehorn E. A., Baumeister K. Complete nucleotide sequence of the AIDS virus, HTLV-III. Nature. 1985 Jan 24;313(6000):277–284. doi: 10.1038/313277a0. [DOI] [PubMed] [Google Scholar]
  17. Rebbe N. F., Hickman W. S., Ley T. J., Stafford D. W., Hickman S. Nucleotide sequence and regulation of a human 90-kDa heat shock protein gene. J Biol Chem. 1989 Sep 5;264(25):15006–15011. [PubMed] [Google Scholar]
  18. Rudensky AYu, Preston-Hurlburt P., Hong S. C., Barlow A., Janeway C. A., Jr Sequence analysis of peptides bound to MHC class II molecules. Nature. 1991 Oct 17;353(6345):622–627. doi: 10.1038/353622a0. [DOI] [PubMed] [Google Scholar]
  19. Verhoeyen M., Fang R., Jou W. M., Devos R., Huylebroeck D., Saman E., Fiers W. Antigenic drift between the haemagglutinin of the Hong Kong influenza strains A/Aichi/2/68 and A/Victoria/3/75. Nature. 1980 Aug 21;286(5775):771–776. doi: 10.1038/286771a0. [DOI] [PubMed] [Google Scholar]
  20. Weeda G., van Ham R. C., Masurel R., Westerveld A., Odijk H., de Wit J., Bootsma D., van der Eb A. J., Hoeijmakers J. H. Molecular cloning and biological characterization of the human excision repair gene ERCC-3. Mol Cell Biol. 1990 Jun;10(6):2570–2581. doi: 10.1128/mcb.10.6.2570. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Winter G., Fields S. The structure of the gene encoding the nucleoprotein of human influenza virus A/PR/8/34. Virology. 1981 Oct 30;114(2):423–428. doi: 10.1016/0042-6822(81)90223-3. [DOI] [PubMed] [Google Scholar]

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