Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1986 Nov 1;164(5):1779–1784. doi: 10.1084/jem.164.5.1779

T cell clones specific for an amphipathic alpha-helical region of sperm whale myoglobin show differing fine specificities for synthetic peptides. A multiview/single structure interpretation of immunodominance

PMCID: PMC2188437  PMID: 3490536

Abstract

The T cell response to sperm whale myoglobin in the H-2d haplotype has been shown to be largely focused on a limited region around glutamic acid 109 recognized in association with I-Ad. T cell clones 9.27 and 1.2 have been previously (4, 5) shown to reflect this specificity and MHC restriction. In this study we have used a panel of synthetic peptides from the region 102-118 of myoglobin to characterize the specificities of these representative clones. The segment from 106-118 was found to represent a consensus region for recognition by both clones. However, we saw significant differences between clones in the hierarchy of responsiveness to peptides within the panel. In as much as the peptide and the I-Ad molecule remain constant, these differences derive from differences in how each T cell receptor interacts with the antigen. This peptide segment is an amphipathic alpha helix in native myoglobin, meaning that one side is hydrophobic and the other hydrophilic. It is one of the prototype cases that led us to find that amphipathic helices constitute the majority of immunodominant sites recognized by helper T cells (1). It is likely that the peptide will refold into an amphipathic helix stabilized by the interface at the surface of the presenting cell. When such secondary conformation is considered, these data are consistent with a model of multiple T cell specificities arising from multiple views of a single antigen conformation at a single Ia-binding site and do not require postulation of multiple conformations or binding sites. Additionally, the finding of distinct specificities suggests that the immunodominance of this site depends not on the dominance of a single clone, but on the focusing of a polyclonal response on a single region of the molecule in association with I-Ad. The immunodominance of this particular region of the protein may thus depend on intrinsic features of the site, such as potential to form an amphipathic helix, as well as extrinsic factors such as binding properties of the I-A molecule.

Full Text

The Full Text of this article is available as a PDF (402.6 KB).

Selected References

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

  1. Allen P. M., Matsueda G. R., Haber E., Unanue E. R. Specificity of the T cell receptor: two different determinants are generated by the same peptide and the I-Ak molecule. J Immunol. 1985 Jul;135(1):368–373. [PubMed] [Google Scholar]
  2. Allen P. M., McKean D. J., Beck B. N., Sheffield J., Glimcher L. H. Direct evidence that a class II molecule and a simple globular protein generate multiple determinants. J Exp Med. 1985 Oct 1;162(4):1264–1274. doi: 10.1084/jem.162.4.1264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Beck B. N., Nelson P. A., Fathman C. G. The I-Ab mutant B6.C-H-2bm12 allows definition of multiple T cell epitopes on I-A molecules. J Exp Med. 1983 May 1;157(5):1396–1404. doi: 10.1084/jem.157.5.1396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Berkower I., Buckenmeyer G. K., Berzofsky J. A. Molecular mapping of a histocompatibility-restricted immunodominant T cell epitope with synthetic and natural peptides: implications for T cell antigenic structure. J Immunol. 1986 Apr 1;136(7):2498–2503. [PubMed] [Google Scholar]
  5. Berkower I., Buckenmeyer G. K., Gurd F. R., Berzofsky J. A. A possible immunodominant epitope recognized by murine T lymphocytes immune to different myoglobins. Proc Natl Acad Sci U S A. 1982 Aug;79(15):4723–4727. doi: 10.1073/pnas.79.15.4723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Berkower I., Kawamura H., Matis L. A., Berzofsky J. A. T cell clones to two major T cell epitopes of myoglobin: effect of I-A/I-E restriction on epitope dominance. J Immunol. 1985 Oct;135(4):2628–2634. [PubMed] [Google Scholar]
  7. Berkower I., Matis L. A., Buckenmeyer G. K., Gurd F. R., Longo D. L., Berzofsky J. A. Identification of distinct predominant epitopes recognized by myoglobin-specific T cells under the control of different Ir genes and characterization of representative T cell clones. J Immunol. 1984 Mar;132(3):1370–1378. [PubMed] [Google Scholar]
  8. Brown M. A., Glimcher L. A., Nielsen E. A., Paul W. E., Germain R. N. T-cell recognition of Ia molecules selectively altered by a single amino acid substitution. Science. 1986 Jan 17;231(4735):255–258. doi: 10.1126/science.3484558. [DOI] [PubMed] [Google Scholar]
  9. Cohn L. E., Glimcher L. H., Waldmann R. A., Smith J. A., Ben-Nun A., Seidman J. G., Choi E. Identification of functional regions on the I-Ab molecule by site-directed mutagenesis. Proc Natl Acad Sci U S A. 1986 Feb;83(3):747–751. doi: 10.1073/pnas.83.3.747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Corley L., Sachs D. H., Anfinsen C. B. Rapid solid-phase synthesis of bradykinin. Biochem Biophys Res Commun. 1972 Jun 28;47(6):1353–1359. doi: 10.1016/0006-291x(72)90221-5. [DOI] [PubMed] [Google Scholar]
  11. DeLisi C., Berzofsky J. A. T-cell antigenic sites tend to be amphipathic structures. Proc Natl Acad Sci U S A. 1985 Oct;82(20):7048–7052. doi: 10.1073/pnas.82.20.7048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dunnill P. The use of helical net-diagrams to represent protein structures. Biophys J. 1968 Jul;8(7):865–875. doi: 10.1016/S0006-3495(68)86525-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lin C. C., Rosenthal A. S., Passmore H. C., Hansen T. H. Selective loss of antigen-specific Ir gene function in IA mutant B6.C-H-2bm12 is an antigen presenting cell defect. Proc Natl Acad Sci U S A. 1981 Oct;78(10):6406–6410. doi: 10.1073/pnas.78.10.6406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Manca F., Clarke J. A., Miller A., Sercarz E. E., Shastri N. A limited region within hen egg-white lysozyme serves as the focus for a diversity of T cell clones. J Immunol. 1984 Oct;133(4):2075–2078. [PubMed] [Google Scholar]
  15. Needleman B. W., Pierres M., Devaux C. A., Dwyer P. N., Finnegan A., Sachs D. H., Hodes R. J. An analysis of functional T cell recognition sites on I-E molecules. J Immunol. 1984 Aug;133(2):589–596. [PubMed] [Google Scholar]
  16. Shastri N., Oki A., Miller A., Sercarz E. E. Distinct recognition phenotypes exist for T cell clones specific for small peptide regions of proteins. Implications for the mechanisms underlying major histocompatibility complex-restricted antigen recognition and clonal deletion models of immune response gene defects. J Exp Med. 1985 Jul 1;162(1):332–345. doi: 10.1084/jem.162.1.332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Shimonkevitz R., Colon S., Kappler J. W., Marrack P., Grey H. M. Antigen recognition by H-2-restricted T cells. II. A tryptic ovalbumin peptide that substitutes for processed antigen. J Immunol. 1984 Oct;133(4):2067–2074. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES