Skip to main content
NCBI home page
Immunology logoLink to Immunology
. 1996 Mar;87(3):414–420. doi: 10.1046/j.1365-2567.1996.458547.x

Role of polymorphic residues of human leucocyte antigen-DR molecules on the binding of human immunodeficiency virus peptides.

S Jurcevic 1, C Praud 1, H L Coppin 1, A Bertrand 1, S Ricard 1, M Thomsen 1, F Lakhdar-Ghazal 1, C De Preval 1
PMCID: PMC1384110  PMID: 8778027

Abstract

A study was made of the binding properties of 96 human immunodeficiency virus peptides to human leucocyte antigen (HLA)-DR1 and HLA-DR103 molecules, which differ by three amino acids at positions 67, 70 and 71 in the beta chains. The affinity of the peptides was characterized by their inhibitory concentrations in competitive binding assays which displace half of the labelled influenza haemagglutinin peptide HA306-318 (IC50). Among the high-affinity peptides (IC50 < or = 1 microM), seven bound to DR1, three to DR103 and five equally well to both alleles (promiscuous peptides). Thirty-two other peptides showed medium or low affinity for DR molecules. The role of polymorphic residues was analysed using six mutated DR molecules, intermediates between DR1 and DR103 and differing by one or two substitutions at positions 67, 70 or 71. We reached the same conclusions when using DR1-specific or DR103-specific peptides: modification of residue 70 had no effect on peptide affinity, but single substitution at positions 67 or 71 decreased the allele specificity of the peptides while double substitution at 67 and 71 completely reversed the peptide specificity. In functional assays, DR-binding peptides are able to outcompete specific T-cell proliferation. Furthermore, modification at position 67 or 70 significantly affects the T-cell response and mutation at position 71 abolishes completely the T-cell proliferation. Thus, the polymorphic positions 67 and 71 contributed to the peptide binding with direct effects on T-cell receptor (TCR) recognition while position 70 seems to be mostly engaged in TCR interactions. Furthermore, our results suggest that polymorphic residues may select allele-specific peptides and also influence the conformation of promiscuous peptides.

Full text

PDF
414

Selected References

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

  1. Ahlers J. D., Pendleton C. D., Dunlop N., Minassian A., Nara P. L., Berzofsky J. A. Construction of an HIV-1 peptide vaccine containing a multideterminant helper peptide linked to a V3 loop peptide 18 inducing strong neutralizing antibody responses in mice of multiple MHC haplotypes after two immunizations. J Immunol. 1993 Jun 15;150(12):5647–5665. [PubMed] [Google Scholar]
  2. Altmann D. M., Heyes J. M., Ikeda H., Sadler A. M., Wilkinson D., Madrigal J. A., Bodmer J. G., Trowsdale J. Fine mapping of HLA class II monoclonal antibody specificities using transfected L cells. Immunogenetics. 1990;32(1):51–55. doi: 10.1007/BF01787329. [DOI] [PubMed] [Google Scholar]
  3. Barber L. D., Bal V., Lamb J. R., O'Hehir R. E., Yendle J., Hancock R. J., Lechler R. I. Contribution of T-cell receptor-contacting and peptide-binding residues of the class II molecule HLA-DR4 Dw10 to serologic and antigen-specific T-cell recognition. Hum Immunol. 1991 Oct;32(2):110–118. doi: 10.1016/0198-8859(91)90107-k. [DOI] [PubMed] [Google Scholar]
  4. Birx D. L., Redfield R. R. Immunotherapeutic strategies in the treatment of HIV infection and AIDS. Curr Opin Immunol. 1993 Aug;5(4):600–607. doi: 10.1016/0952-7915(93)90044-s. [DOI] [PubMed] [Google Scholar]
  5. Buus S., Sette A., Colon S. M., Jenis D. M., Grey H. M. Isolation and characterization of antigen-Ia complexes involved in T cell recognition. Cell. 1986 Dec 26;47(6):1071–1077. doi: 10.1016/0092-8674(86)90822-6. [DOI] [PubMed] [Google Scholar]
  6. Chicz R. M., Urban R. G., Lane W. S., Gorga J. C., Stern L. J., Vignali D. A., Strominger J. L. Predominant naturally processed peptides bound to HLA-DR1 are derived from MHC-related molecules and are heterogeneous in size. Nature. 1992 Aug 27;358(6389):764–768. doi: 10.1038/358764a0. [DOI] [PubMed] [Google Scholar]
  7. Coppin H. L., Avoustin P., Fabron J., Huchenq A., Garnier J. M., Thomsen M., De Preval C. Evolution of the HLA-DR1 gene family. Structural and functional analysis of the new allele "DR-BON". J Immunol. 1990 Feb 1;144(3):984–989. [PubMed] [Google Scholar]
  8. Coppin H. L., Carmichael P., Lombardi G., L'Faqihi F. E., Salter R., Parham P., Lechler R. I., de Preval C. Position 71 in the alpha helix of the DR beta domain is predicted to influence peptide binding and plays a central role in allorecognition. Eur J Immunol. 1993 Feb;23(2):343–349. doi: 10.1002/eji.1830230207. [DOI] [PubMed] [Google Scholar]
  9. Hammer J., Takacs B., Sinigaglia F. Identification of a motif for HLA-DR1 binding peptides using M13 display libraries. J Exp Med. 1992 Oct 1;176(4):1007–1013. doi: 10.1084/jem.176.4.1007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hill C. M., Hayball J. D., Allison A. A., Rothbard J. B. Conformational and structural characteristics of peptides binding to HLA-DR molecules. J Immunol. 1991 Jul 1;147(1):189–197. [PubMed] [Google Scholar]
  11. Hill C. M., Liu A., Marshall K. W., Mayer J., Jorgensen B., Yuan B., Cubbon R. M., Nichols E. A., Wicker L. S., Rothbard J. B. Exploration of requirements for peptide binding to HLA DRB1*0101 and DRB1*0401. J Immunol. 1994 Mar 15;152(6):2890–2898. [PubMed] [Google Scholar]
  12. Hunt D. F., Michel H., Dickinson T. A., Shabanowitz J., Cox A. L., Sakaguchi K., Appella E., Grey H. M., Sette A. Peptides presented to the immune system by the murine class II major histocompatibility complex molecule I-Ad. Science. 1992 Jun 26;256(5065):1817–1820. doi: 10.1126/science.1319610. [DOI] [PubMed] [Google Scholar]
  13. Jardetzky T. S., Gorga J. C., Busch R., Rothbard J., Strominger J. L., Wiley D. C. Peptide binding to HLA-DR1: a peptide with most residues substituted to alanine retains MHC binding. EMBO J. 1990 Jun;9(6):1797–1803. doi: 10.1002/j.1460-2075.1990.tb08304.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jensen P. E. Regulation of antigen presentation by acidic pH. J Exp Med. 1990 May 1;171(5):1779–1784. doi: 10.1084/jem.171.5.1779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lanzavecchia A. Identifying strategies for immune intervention. Science. 1993 May 14;260(5110):937–944. doi: 10.1126/science.8493532. [DOI] [PubMed] [Google Scholar]
  16. Lombardi G., Barber L., Sidhu S., Batchelor J. R., Lechler R. I. The specificity of alloreactive T cells is determined by MHC polymorphisms which contact the T cell receptor and which influence peptide binding. Int Immunol. 1991 Aug;3(8):769–775. doi: 10.1093/intimm/3.8.769. [DOI] [PubMed] [Google Scholar]
  17. O'Sullivan D., Arrhenius T., Sidney J., Del Guercio M. F., Albertson M., Wall M., Oseroff C., Southwood S., Colón S. M., Gaeta F. C. On the interaction of promiscuous antigenic peptides with different DR alleles. Identification of common structural motifs. J Immunol. 1991 Oct 15;147(8):2663–2669. [PubMed] [Google Scholar]
  18. O'Sullivan D., Sidney J., Appella E., Walker L., Phillips L., Colón S. M., Miles C., Chesnut R. W., Sette A. Characterization of the specificity of peptide binding to four DR haplotypes. J Immunol. 1990 Sep 15;145(6):1799–1808. [PubMed] [Google Scholar]
  19. Olson R. R., De Magistris M. T., Di Tommaso A., Karr R. W. Mutations in the third, but not the first or second, hypervariable regions of DR(beta 1*0101) eliminate DR1-restricted recognition of a pertussis toxin peptide. J Immunol. 1992 May 1;148(9):2703–2708. [PubMed] [Google Scholar]
  20. Rammensee H. G. Chemistry of peptides associated with MHC class I and class II molecules. Curr Opin Immunol. 1995 Feb;7(1):85–96. doi: 10.1016/0952-7915(95)80033-6. [DOI] [PubMed] [Google Scholar]
  21. Roche P. A., Cresswell P. High-affinity binding of an influenza hemagglutinin-derived peptide to purified HLA-DR. J Immunol. 1990 Mar 1;144(5):1849–1856. [PubMed] [Google Scholar]
  22. Sette A., Southwood S., O'Sullivan D., Gaeta F. C., Sidney J., Grey H. M. Effect of pH on MHC class II-peptide interactions. J Immunol. 1992 Feb 1;148(3):844–851. [PubMed] [Google Scholar]
  23. Stern L. J., Brown J. H., Jardetzky T. S., Gorga J. C., Urban R. G., Strominger J. L., Wiley D. C. Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature. 1994 Mar 17;368(6468):215–221. doi: 10.1038/368215a0. [DOI] [PubMed] [Google Scholar]
  24. Stern L. J., Wiley D. C. The human class II MHC protein HLA-DR1 assembles as empty alpha beta heterodimers in the absence of antigenic peptide. Cell. 1992 Feb 7;68(3):465–477. doi: 10.1016/0092-8674(92)90184-e. [DOI] [PubMed] [Google Scholar]
  25. Wordsworth B. P., Bell J. I. The immunogenetics of rheumatoid arthritis. Springer Semin Immunopathol. 1992;14(1):59–78. doi: 10.1007/BF00197132. [DOI] [PubMed] [Google Scholar]

Articles from Immunology are provided here courtesy of British Society for Immunology

RESOURCES