Molecular Features of Class II MHC-Restricted T-Cell Recognition of Protein and Peptide Antigens: The Importance of Amphipathic Structures

  • J. A. Berzofsky
  • J. Cornette
  • H. Margalit
  • I. Berkower
  • K. Cease
  • C. DeLisi
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 130)


Much work has been done on the use of peptides as immunogens, but most has concentrated on antibody production (reviewed in LERNER 1984; ARNON 1984) rather than T-cell responses. There are certain potential problems with their use for antibody production that do not apply to T cells. Antibodies raised against peptides as immunogens generally cross-react with the native protein from which the peptides were derived with affinities several Orders of magnitude lower than those for the peptide (reviewed in BERZOFSKY 1985 a). Conversely, antibodies raised against the native protein generally cross-react with peptides derived from it with a lower affinity, although exceptions have been noted (LANDO and REICHLIN 1982). In both directions, cross-reactions seem to be most easily measured when the peptide corresponds to a more mobile portion of the protein (TAINER et al. 1984, 1985; WESTHOF et al. 1984); perhaps such portions are better able to share some conformational states with the peptide so that one can achieve an induced fit with antibodies made against the other (BERZOFSKY 1985 a). In addition, there are antibodies made against the native protein that react with assembled topographic determinants consisting of amino acid residues far apart in the primary sequence that are brought together on the surface of the native molecule as it folds in its native conformation (BENJAMIN et al. 1984; BERZOFSKY 1985a). Such antigenic sites exist only on the surface topography of the native protein, and thus do not exist in any peptide segment of the protein.


Native Protein Antigenic Site Sperm Whale Hydrophobicity Scale Mouth Disease Virus 
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  1. Allen PM, Strydom DJ, Unanue ER (1984) Processing of lysozyme by macrophages; identification of the determinant recognized by two T cell hybridomas. Proc Natl Acad Sei USA 81:2489–2493CrossRefGoogle Scholar
  2. Arnon R (1984) Antigenic determinants of proteins and synthetic vaccines. In:Schechter AN, Dean A, Goldberger RF (eds) Impact of protein chemistry on the biomedical sciences. Academic, Orlando, p 187Google Scholar
  3. Benacerraf B (1978) A hypothesis to relate the specificity of T lymphocytes and the activity of I region-speeifie Ir genes in macrophages and B lymphocytes. J Immunol 120:1809–1812PubMedGoogle Scholar
  4. Benjamin DC, Berzofsky JA, East IJ, Gurd FRN, Hannum C, Leach SJ, Margoliash E, Michael JG, Miller A, Prager EM, Reichlin M, Sercarz EE, Smith-Gill SJ, Todd PE, Wilson AC (1984) The antigenic strueture of proteins:a reappraisal. Annu Rev Immunol 2:67–101PubMedCrossRefGoogle Scholar
  5. Berkower I, Buckenmeyer GK, Gurd FRN, Berzofsky JA (1982) A possible immunodominant epitope recognized by murine T lymphocytes immune to different myoglobins. Proc Natl Acad Sei USA 79:4723–4727CrossRefGoogle Scholar
  6. Berkower I, Matis LA, Buckenmeyer GK, Gurd FRN, Longo DL, Berzofsky JA (1984) Identification of distinet predominant epitopes recognized by myoglobin specific T cells under the control of different Ir genes and characterization of representative T cell clones. J Immunol 132:1370–1378PubMedGoogle Scholar
  7. Berkower I, Kawamura H, Matis LA, Berzofsky JA (1985) T cell clones to two major T cell epitopes of myoglobin:Effect of I-A/I-E restriction on epitope dominance. J Immunol 135:2628–2634Google Scholar
  8. Berkower I, Buckenmeyer GK, Berzofsky JA (1986) Moleeular mapping of a histocompatibility- restricted immunodominant T cell epitope with synthetic and natural peptides:implications for T cell antigenic strueture. J Immunol 136:2498–2503PubMedGoogle Scholar
  9. Berzofsky JA (1980) Immune response genes in the regulation of mammalian immunity. In:Goldberger RF (ed) Biological regulation and development, vol II. Plenum, New York, pp 467–594Google Scholar
  10. Berzofsky JA (1985 a) Intrinsic and extrinsic factors in protein antigenic strueture. Science 229:932–940PubMedCrossRefGoogle Scholar
  11. Berzofsky JA (1985b) The nature and role of antigen processing in T cell activation. In:CruseGoogle Scholar
  12. J, Lewis R (eds) The year in immunology 1984–85. Karger, Basel, pp 18–24Google Scholar
  13. Berzofsky JA (1986) Ir genes:antigen-speeifie genetic regulation of the immune response. In:Sela M (ed) The antigens. Academic, New York (to be published)Google Scholar
  14. Berzofsky JA, Hicks G, Fedorko J, Minna J (1980) Properties of monoclonal antibodies specific for determinants ofa protein antigen, myoglobin. J Biol Chem 255:11188–11191PubMedGoogle Scholar
  15. Berzofsky JA, Buckenmeyer GK, Hicks G, Gurd FRN, Feldmann RJ, Minna J (1982) Topographie antigenic determinants recognized by monoclonal antibodies to sperm whale myoglobin. J Biol Chem 257:3189–3198PubMedGoogle Scholar
  16. Cease KB, Berkower I, York-Jolley J, Berzofsky JA (1986) Characterization of differing T cell specificities for an immunodominant site in sperm whale myoglobin using synthetic peptides. Fed Proc 45:619Google Scholar
  17. Chou PY, Fasman GD (1978) Empirical predictions of protein conformation. Annu Rev Biochem 47:251–276PubMedCrossRefGoogle Scholar
  18. Cornette JL, Cease KB, Margalit H, Spouge JL, Berzofsky JA, DeLisi C (1986) Hydrophobicity scales and computational techniques for detecting amphipathic struetures in proteins. In preparationGoogle Scholar
  19. Corradin GP, Juillerat MA, Vita C, Engers HD (1983) Fine specificity of a BALB/c T cell clone directed against beef apo cytochrome c. Mol Immunol 20:763–768PubMedCrossRefGoogle Scholar
  20. DeLisi C, Berzofsky JA (1985) T cell antigenic sites tend to be amphipathic structures. Proc Natl Acad Sei USA 82:7048–7052CrossRefGoogle Scholar
  21. DeLisi C, Cornette J, Margalit H, Cease K, Spouge J, Berzofsky JA (1986) The role of amphipathicity as an indicator of T cell antigenic sites on proteins. In:Sercarz EE, Berzofsky JA (eds) Immunogenicity of protein antigens:repertoire and regulation. CRC, Boca Raton (to be published)Google Scholar
  22. Dorow DS, Shi P-T, Carbone FR, Minasian E, Todd PEE, Leach SJ (1985) Two large immunogenic and antigenic myoglobin peptides and the effects of cyclisation. Mol Immunol 22:1255–1264PubMedCrossRefGoogle Scholar
  23. East IJ, Hurrell JGR, Todd PEE, Leach SJ (1982) Antigenic specificity of monoclonal antibodies to human myoglobin. J Biol Chem 257:3199–3202PubMedGoogle Scholar
  24. Francis MJ, Fry CM, Rowlands DJ, Brown F, Bittie JL, Houghten RA, Lerner RA (1985) Immunologie priming with synthetic peptides of foot and mouth disease virus. J Gen Virol 66:2347–2354PubMedCrossRefGoogle Scholar
  25. Garnier J, Osguthorpe DJ, Robson B (1978) Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins. J Mol Biol 120:97–120.PubMedCrossRefGoogle Scholar
  26. Gell PGH, Benacerraf B (1959) Studies on hypersensitivity. II. Delayed hypersensitivity to denatured proteins in guinea pigs. Immunology 2:64–70Google Scholar
  27. Godfrey WL, Lewis GK, Goodman JW (1984) The anatomy of an antigen molecule:FunctionalGoogle Scholar
  28. subregions of L-tyrosine-p-azobenzenearsonate. Mol Immunol 21:969–978Google Scholar
  29. Kimoto M, Fathman CG (1980) Antigen-reactive T cell clones. I. Transcomplementing hybrid I-A-region gene products function effectively in antigen presentation. J Exp Med 152:759–770Google Scholar
  30. Klein P, DeLisi C (1986) Prediction of protein structural class from the amino acid sequence. Biopolymers (to be published)Google Scholar
  31. Kyte J, Doolittle RF (1982) A simple method for displaying the hydropathic character of a protein. J Mol Biol 157:105–132PubMedCrossRefGoogle Scholar
  32. Lando G, Reichlin M (1982) Antigenic structure of sperm whale myoglobin. II. Characterization of antibodies preferentially reactive with peptides arising in response to immunization with the native protein. J Immunol 129:212–216Google Scholar
  33. Lando G, Berzofsky JA, Reichlin M (1982) Antigenic structure of sperm whale myoglobin. I. Partition of specificities between antibodies reactive with peptides and native protein. J Immunol 129:206–211Google Scholar
  34. Lerner RA (1984) Antibodies of predetermined specificity in biology and medicine. Adv Immunol 36:1–44PubMedCrossRefGoogle Scholar
  35. Margalit H, Spouge JL, Cornette JL, Cease K, DeLisi C, Berzofsky JA (1986) Prediction of T-cell antigenic sites from the primary sequence. (in preparation)Google Scholar
  36. Milich DR, McLachlan A, McNamara MK, Chisari FV, Thornton GB (1986) T and B cell recognition of native and synthetic pre-S region determinants on HBsAg. In:Brown F, Chanock R, Lerner RA (eds) New approaches to immunization. Cold Spring Harbor Laboratories, New York, pp 377–382Google Scholar
  37. Pincus MR, Gerewitz F, Schwartz RH, Scheraga HA (1983) Correlation between the conformation of cytochrome c peptides and their stimulatory activity in a T-lymphocyte proliferation assay. Proc Natl Acad Sei USA 80:3297–3300CrossRefGoogle Scholar
  38. Rose GD, Geselowitz AR, Lesser GJ, Lee RH, Zehfus MH (1985) Hydrophobicity of amino acid residues in globular proteins. Science 229:834–838PubMedCrossRefGoogle Scholar
  39. Rosenthal AS (1978) Determinant selection and macrophage function in genetic control of the immune response. Immunol Rev 40:136–156PubMedCrossRefGoogle Scholar
  40. Schwartz RH, Fox BS, Fraga E, Chen C, Singh B (1985) The T lymphocyte response to cytochrome c. V. Determination of the minimal peptide size required for Stimulation of T cell clones and assessment of the contribution of each residue beyond this size to antigenic potency. J Immunol 135:2598–2608Google Scholar
  41. Staudt LM, Gerhard W (1983) Generation of antibody diversity in the immune response of BALB/c mice to influenza virus hemagglutinin. I. Signiflcant Variation in repertoire expression between individual mice. J Exp Med 157:687–704PubMedCrossRefGoogle Scholar
  42. Streicher HZ, Berkower IJ, Busch M, Gurd FRN, Berzofsky JA (1984) Antigen conformation determines processing requirements for T cell activation. Proc Natl Acad Sei USA 81:6831–6835CrossRefGoogle Scholar
  43. Tainer JA, Getzoff ED, Alexander H, Houghten RA, Olson AJ, Lerner RA, Hendrickson WA (1984) The reactivity of anti-peptide antibodies is a function of the atomic mobility of sites in a protein. Nature 312:127–133PubMedCrossRefGoogle Scholar
  44. Tainer JA, Getzoff ED, Paterson Y, Olson AJ, Lerner RA (1985) The atomic mobility component of protein antigenicity. Annu Rev Immunol 3:501–535PubMedCrossRefGoogle Scholar
  45. Todd PEE, East IJ, Leach SJ (1982) The immunogenicity and antigenicity of proteins. Trends Biochem Sei 7:212–216CrossRefGoogle Scholar
  46. Unanue ER (1984) Antigen-presenting function of the macrophage. Annu Rev Immunol 2:395–428PubMedCrossRefGoogle Scholar
  47. Watts TH, Gariepy J, Schoolnik GK, McConnell HM (1985) T-cell activation by peptide antigen:effect of peptide sequence and method of antigen presentation. Proc Natl Acad Sei USA 82:5480–5484CrossRefGoogle Scholar
  48. Westhof E, Altschuh D, Moras D, Bloomer AC, Mondragon A, Klug A, Van Regenmortel MHV (1984) Correlation between segmental mobility and the location of antigenic determinants in proteins. Nature 311:123–126PubMedCrossRefGoogle Scholar
  49. Wiley DC, Wilson IA, Skehel JJ (1981) Structural identification of the antibody-binding sites of Hong Kong influenza haemagglutinin and their involvement in antigenic Variation. Nature 289:373–378PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1986

Authors and Affiliations

  • J. A. Berzofsky
    • 1
  • J. Cornette
    • 1
  • H. Margalit
    • 1
  • I. Berkower
    • 1
  • K. Cease
    • 1
  • C. DeLisi
    • 1
  1. 1.Metabolism Branch and Laboratory of Mathematical BiologyNational Cancer Institute, National Institutes of HealthBethesdaUSA

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