The Role of Amino Acid Position and Side Chain Structure in Serological and CTL-Defined Epitopes on the HLA-A2.1 Molecule

  • K. T. Hogan
  • C. Clayberger
  • N. Shimojo
  • W. E. Biddison
  • A. M. Krensky
  • V. H. Engelhard
Conference paper


A major focus of current immunological research is to determine the structure-function relationships of class I MHC molecules. The determination of the three-dimensional structure of HLA-A2.1 by Bjorkman et al. (1987a, 1987b) has significantly advanced our ability to achieve this goal. The α3 domain, which composes the membrane proximal region of the molecule, has a structure similar to that of the constant region of immunoglobulin, and primarily associates with β2- microglobulin. The membrane distal region consists of the α1 and α2 domains which interact to form a β-sheet platform, on top of which reside two antiparallel α-helices that are separated by a long groove. It was hypothesized that this groove acts as the binding site for peptides that are recognized by the TCR in association with class I molecules and in fact, an unidentified peptide(s) was associated with this groove in the crystal structure. An analysis of the crystallographic structure of HLA-A2.1 reveals that nearly all of the side chains of the polymorphic residues are oriented such that they point into the groove of the molecule and thus could be important in mediating contact with peptide, or they point upward from the α-helices and may thus be important in interacting with the TCR (Parham et al. 1988).


Mutant Molecule United State Public Health Service Membrane Proximal Region Peptide Binding Pocket Serological Epitope 
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  1. Ajitkumar P, Geier SS, Kesari KV, Borriello F, Nakagawa M, Bluestone JA, Saper MA, Wiley DC, Nathenson SG (1988) Evidence that multiple residues on both the α-helices of the class I MHC molecule are simultaneously recognized by the T cell receptor. Cell 54: 47–56PubMedCrossRefGoogle Scholar
  2. Bernhard EJ, Le AT, Barbosa JA, Lacy E, Engelhard VH (1988) Cytotoxic T cells from HLA-A2 transgenic mice specific for HLA-A2 expressed on human cells. J Exp Med 168: 1157–1162PubMedCrossRefGoogle Scholar
  3. Bernhard EJ, Le AT, Yannelli JR, Holterman MJ, Hogan KT, Parham P, Engelhard VH (1987) The ability of cytotoxic T cells to recognize HLA-A2.1 or HLA-B7 antigen expressed on murine cells correlates with their epitope specificity. J Immunol 139: 3614–3621PubMedGoogle Scholar
  4. Bjorkman PJ, Saper MA, Samraouri B, Bennet WS, Strominger JL, Wiley DC (1987a) Structure of the human class I histocompatibility antigen, HLA-A2. Nature 329: 506–512PubMedCrossRefGoogle Scholar
  5. Bjorkman PJ, Saper MA, Samraouri B, Bennet WS, Strominger JL, Wiley DC (1987b) The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature 329: 512–518PubMedCrossRefGoogle Scholar
  6. Brodsky FM, Parham P, Barnstable CJ, Crumpton MJ, Bodmer WF (1979) Monoclonal antibodies for analysis of the HLA system. Immunological Rev 47: 3–61CrossRefGoogle Scholar
  7. Clayberger C, Holmes N, Wang PL, Koller TD, Parham P, Krensky AM (1985) Determinants recognized by human cytotoxic T cells on a natural hybrid class I HLA molecule. J Exp Med 162: 1707–1714CrossRefGoogle Scholar
  8. Cowan EP, Jelachich ML, Coligan JE, Biddison WE (1987) Site-directed mutagenesis of an HLA-A3 gene identifies amino acid 152 as crucial for major histocompatibility complex-restricted and alloreactive cytotoxic T-lymphocyte recognition. Proc Natl Acad Sci USA 84: 5014–5018PubMedCrossRefGoogle Scholar
  9. Gotch F, Rothbard J, Howland K, Townsend A, McMichael, A. (1987) Cytotoxic T lymphocytes recognize a fragment of influenza virus matrix protein in association with HLA-A2. Nature 326: 881–882PubMedCrossRefGoogle Scholar
  10. Herman A, Parham P, Weissman SM, Engelhard VH (1983) Recognition by xenogeneic cytotoxic T lymphocytes of cells expressing HLA-A2 or HLA- B7 after DNA-mediated gene transfer. Proc Natl Acad Sci USA 80: 5056–5060PubMedCrossRefGoogle Scholar
  11. Hogan KT, Clayberger C, Bernhard EJ, Walk SF, Ridge JP, Parham P, Krensky AM, Engelhard VH (1988a) Identification by site-directed mutagenesis of amino acid residues contributing to serologic and CTL- defined epitope differences between HLA-A2.1 and HLA-A2.3. J Immunol 141: 2519–2525PubMedGoogle Scholar
  12. Hogan KT, Clayberger C, Bernhard EJ, Walk SF, Ridge JP, Parham P, Krensky AM, Engelhard VH (1989) A panel of unique HLA-A2 mutant molecules defines epitopes recognized by HLA-A2 specific antibodies and CTL. J Immunol 142: 2097–2104PubMedGoogle Scholar
  13. Hogan KT, Clayberger C, Le AT, Ridge JP, Walk SF, Parham P, Krensky AM, Engelhard VH (1988b) CTL-defined epitope differences between HLA-A2.1 and HLA-A2.2 map to two distinct regions of the molecule. J Immunol 141: 4005–4011PubMedGoogle Scholar
  14. Hogan KT, Shimojo N, Walk SF, Engelhard VH, Maloy WE, Coligan JE, Biddison WE (1988c) Mutations in the a-2 helix of HLA-A2 affect presentation but do not inhibit binding of influenza virus matrix peptide. J Exp Med 168: 725–736PubMedCrossRefGoogle Scholar
  15. Holmes N, Ennis P, Wan AM, Denney DW, Parham P (1987) Multiple genetic mechanisms have contributed to the generation of the HLA-A2/A28 family of class I MHC molecules. J Immunol 139: 936–941PubMedGoogle Scholar
  16. Jelachich ML, Cowan EP, Turner RV, Coligan JE, Biddison WE (1988) Analysis of the molecular basis of HLA-A3 recognition by cytotoxic T cells using defined mutants of the HLA-A3 molecule. J Immunol 141: 1108–1113PubMedGoogle Scholar
  17. McMichael AJ, Parham P, Rust N Brodsky F (1980) A monoclonal antibody that recognizes an antigenic determinant shared by HLA-A2 and B17. Hum Immunol 1: 121–129PubMedCrossRefGoogle Scholar
  18. Monos DS, Tekolf WA, Shaw S, Cooper ML (1984) Comparison of structural and functional variation in class I HLA molecules: The role of charged amino acid substitutions. J Immunol 132: 1379–1385PubMedGoogle Scholar
  19. Nathenson SG, Geliebter J, Pfaffenbach GM, Zeff RA (1986) Murine major histocompatibility complex class-I mutants: Molecular Analysis and Structure-Function Implications. Ann Rev Immunol 4: 471–502CrossRefGoogle Scholar
  20. Parham P, Lomen CE, Lawlor DA, Ways JP, Holmes N, Coppin HL, Salter RD, Wan AM, Ennis PD (1988) Nature of polymorphism in HLA-A, -B, and -C molecules. Proc Natl Acad Sci USA 85: 4005–4009PubMedCrossRefGoogle Scholar
  21. Russo C, Ng A-K, Pellegrino MA, Ferrone S (1983) The monoclonal antibody CR11-351 discriminates HLA-A2 variants identified by T cells. Immunogenetics 18: 23–35PubMedCrossRefGoogle Scholar
  22. Shimojo N, Cowan EP, Engelhard VH, Maloy WL, Coligan JE, Biddison WE (1989) A single amino acid substitution in HLA-A2 can alter the selection of the CTL repertoire that responds to influenza virus matrix peptide 55–73. J Immunol 143: 558–564PubMedGoogle Scholar
  23. Storkus W, Howell DN, Salter RD, Dawson JR, Cresswell P (1987) NK susceptibility varies inversely with target cell class I HLA antigen expression. J Immunol 138: 1657–1659PubMedGoogle Scholar
  24. Vega MA, Ezquerra A, Rojo S, Aparicio P, Bragado R, Lopez de Castro JA (1985) Structural analysis of an HLA-B27 functional variant: Identification of residues that contribute to the specificity of recognition of cytolytic T lymphocytes. Proc Natl Acad Sci USA 82: 7394–7398PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1990

Authors and Affiliations

  • K. T. Hogan
    • 1
  • C. Clayberger
    • 2
  • N. Shimojo
    • 3
  • W. E. Biddison
    • 3
  • A. M. Krensky
    • 2
  • V. H. Engelhard
    • 4
  1. 1.Department of MicrobiologyMedical College of WisconsinMilwaukeeUSA
  2. 2.Department of PediatricsStanford UniversityStanfordUSA
  3. 3.Neuroimmunology Branch, NINCDSNIHBethesdaUSA
  4. 4.Department of MicrobiologyUniversity of VirginiaCharlottesvilleUSA

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