Advertisement

Immunogenetics

, Volume 39, Issue 4, pp 230–242 | Cite as

Pool sequencing of natural HLA-DR, DQ, and DP ligands reveals detailed peptide motifs, constraints of processing, and general rules

  • Kirsten Falk
  • Olaf Rötzschke
  • Stefan Stevanovíc
  • Günther Jung
  • Hans-Georg Rammensee
Original Articles

Abstract

We have approached the problem of MHC class II ligand motifs by pool sequencing natural peptides eluted from HLA-DR, DQ, and DP molecules. The results indicate surprisingly clear patterns, although not quite as clear as with natural class I ligands. The most striking feature is a highly dominant Proline at position 2. We interpret this to be a consequence of aminopeptidase N-like activity in processing. Another general aspect is the existence of three to four hydrophobic or aromatic anchors, whereby the first and the last are separated by five to eight residues. The peptide motifs for HLA-DR1, DR5, DQ7, and DPw4 are allele-specific and differ by spacing and occupancy of anchors. The anchors tend to be flanked by clusters of charged residues, and small residues, especially Ala, are frequent in the motif centers. These detailed motifs allow one to interpret most previous (DR-) motifs as fitting one or more of the anchors or conserved clusters. The relative motif symmetry suggests the possibility of bidirectional binding of peptides in the class II groove.

Keywords

Peptide Proline General Rule Striking Feature Clear Pattern 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Alexander, J., Payne, J. A., Shigekawa, B., Frelinger, J. A., and Cresswell, P. The transport of class I major histocompatibility complex antigens is determined by sequences in the α1 and α2 protein domains. Immunogenetics 31: 169–178, 1990Google Scholar
  2. Ansorge, S., Schön, E., and Kunz, D., Membrane-bound peptidases of lymphocytes — functional implications. Biomedica Biochimica Acta 50: 799–807, 1991Google Scholar
  3. Bodmer, J. G., Albert, E. D., Bodmer, W. F., Dupont, B., Erlich, H. A., Mach, B., Marsh, S. G. E., Mayr, W. R., Parham, P., Sasasuki, T., Schreuder, G. M. T., Strominger, J. L., et al. Nomenclature for factors of the HLA system, 1991. Immunogenetics 36: 135–148, 1992Google Scholar
  4. Brown, J. H., Jardetzky, T., Saper, M. A., Samraoui, B., Bjorkman, P. J., and Wiley, D. C. A hypothetical model of the foreign antigen binding site of class II histocompatibility molecules. Nature 332: 845–850, 1988CrossRefPubMedGoogle Scholar
  5. Brown, J. H., Jardetzky, T. S., Gorga, J. C., Stern, L. J., Urban, R. G., Strominger, J. L., and Wiley, D. C. Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature 364: 33–39, 1993CrossRefPubMedGoogle Scholar
  6. Chicz, R. M., Urban, R. G., Lane, W. S., Gorga, J. C., Stern, L. J., Vignali, D. A. A., and Strominger, J. L. Predominant naturally processed peptides bound to HLA-DR1 are derived from MHC-related molecules and are heterogeneous in size. Nature 358: 764–768, 1992Google Scholar
  7. DeMars, R., Rudersdorf, R., Chang, C., Petersen, J., Strandtmann, J., Korn, N., Sidwell, B., and Orr, H. T. Mutations that impair a posttranscriptional step in expression of HLA-A and-B antigens. Proc Natl Acad Sci USA 82: 8183–8187, 1985Google Scholar
  8. Demotz, S., Barbey, C., Corradin, G., Amoroso, A., and Lanzavecchia, A. The set of naturally processed peptides displayed by DR molecules is tuned by polymorphism of residue 86. Eur J Immunol 23: 425–432, 1993Google Scholar
  9. Falk, K., Rötschke, O., Stevanović, S., Jung, G., and Rammensee, H.-G. Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature 351: 290–296, 1991Google Scholar
  10. Fremont, D. H., Matsamura, M., Stura, E. A., Peterson, P. A., and Wilson, I. A. Crystal structures of two viral peptides in complex with murine MHC class I H-2Kb. Science 257: 919–927, 1992Google Scholar
  11. Garrett, T. P. J., Saper, M. A., Bjorkman, P. J., Strominger, J. L., and Wiley, D. C. Specificity pockets for the side chains of peptide antigens in HLA-Aw68. Nature 342: 692–696, 1989Google Scholar
  12. Gorga, J. C. Structural analysis of class II major histocompatibility complex proteins. CRC Crit Rev Immunol 11(5): 305–335, 1992Google Scholar
  13. Gorga, J. C., Horejsi, V., Johnson, D. R., Raghupathy, R., and Strominger, J. L. Purification and characterization of class II histocompatibility antigens from a homozygous human B cell line. J Biol Chem 262: 16087–16094, 1987Google Scholar
  14. Gorga, J. C., Knudsen, P. J., Foran, J. A., Strominger, J. L., and Burakoff, S. J. Immunochemically purified DR antigens in liposomes stimulate xenogeneic cytolytic T cells in secondary in vitro cultures. Cell Immunol 103: 160–173, 1986Google Scholar
  15. Guo, H. C., Jardetzky, T. S., Garrett, T. P. J., Lane, W. S., Strominger, J. L., and Wiley, D. C. Different length peptides bind to HLA-Aw68 similarly at their ends but bulge out in the middle. Nature 360: 364–366, 1992Google Scholar
  16. Hammer, J., Takacs, B., and Sinigaglia, F. Identification of a motif for HLA-DR1 binding peptides using M13 display libraries. J Exp Med 176: 1007–1013, 1992Google Scholar
  17. Hill, C. M., Hayball, J. D., Allison, A. A., and Rothbard, J. B. Conformatinal and structural characteristics of peptides binding to HLA-DR molecules. J Immunol 147: 189, 1991Google Scholar
  18. Hunt, D. F., Michel, H., Dickinson, T. A., Shabanowitz, J., Cox, A. L., Sakaguchi, K., Appella, E., Grey, H. M., and Sette, A. Peptides presented to the immune system by the murine class II major histocompatibility complex molecule I-Ad. Science 256: 1817–1820, 1992Google Scholar
  19. Jardetzky, T. S., Gorga, J. C., Busch, R., Rothbard, J., Strominger, J. L., and Wiley, D. C. Peptide binding to HLA-DR1: A peptide with most residues substituted to alanine retains MHC binding. EMBO J 9: 1797–1803, 1990Google Scholar
  20. Jardetzky, T. S., Lane, W. S., Robinson, R. A., Madden, D. R., and Wiley, D. C. Identification of self peptides bound to purified HLA-B27. Nature 353: 326–329, 1991Google Scholar
  21. Krieger, J. E., Karr, R. W., Grey, H. M., Yu, W. Y., O'Sullivan, D., Batorsky, L., Zheng, Z. L., Colon, S. M., Gaeta, F. C. A., Sidney, J., Albertson, M., Del Guercio, M. F., Chesnut, R. W., and Sette, A. Single amino acid changes in DR and antigen define residues critical for peptide-MHC binding and T cell recognition. J Immunol 146: 2331, 1991Google Scholar
  22. Kropshofer, H., Max, H., Müller, C. A., Hesse, F., Stevanović, S., Jung, G., and Kalbacher, H. Self-peptide released from class II HLA-DR1 exhibits a hydrophobic two-residue contact motif. J Exp Med 175: 1799–1803, 1992Google Scholar
  23. Kyte, J. and Doolittle, R. F. A simple method for displaying the hydrophatic character of a protein. J Mol Biol 157: 105–132, 1982PubMedGoogle Scholar
  24. Lampson, L. A. and Levy, R. Two populations of la-like molecules on a human B cell line. J Immunol 125: 293–299, 1980Google Scholar
  25. Madden, D. R., Gorga, J. C., Strominger, J. L., and Wiley, D. C. The structure of HLA-B27 reveals nonamer self-peptides bound in an extended conformation. Nature 353: 321–325, 1991Google Scholar
  26. Malcharek, G., Falk, K., Rötzschke, O., Rammensee, H.-G., Stevanović, S., Gnau, V., Jung, G., and Melms, A. Natural peptide ligand motifs of two HLA molecules associated with myasthenia gravis. Int Immunol 5: 1229–1237, 1993Google Scholar
  27. Matsamura, M., Fremont, D. H., Peterson, P., Wilson, I. A. Emerging principles for the recognition of peptide antigens by MHC class I molecules. Science 257: 927–934, 1992aGoogle Scholar
  28. Matsumura, M., Saito, Y., Jackson, M. R., Song, E. S., and Peterson, P. A. In vitro peptide binding to soluble empty class I major histocompatibility complex molecules isolated from transfected Drosophila melanogaster cells. J Biol Chem 267: 23 589–23 595, 1992bGoogle Scholar
  29. Nelson, C. A., Roof, R. W., McCourt, D. W., and Unanue, E. R. Identification of the naturally processed form of hen egg white lysozyme bound to the murine major histocompatibility complex class II molecule I-Ak. Proc Natl Acad Sci USA 89: 7380–7383, 1992Google Scholar
  30. O'Sullivan, D., Arrhenius, T., Sidney, J., Del Guercio, M. F., Albertson, M., Wall, M., Oseroff, C., Southwood, S., Colon, S. M., Gaeta, F. C. A., and Sette, A. On the interaction of promiscuous antigenic peptides with different DR alleles. Identification of common structural motifs. J Immunol 147: 2663–2669, 1991Google Scholar
  31. Panina-Bordignon, P., Tan, A., Termijtelen, A., Demotz, S., Corradin, G., and Lanzavecchia, A. Universally immunogenic T cell epitopes: Promiscuous binding to human MHC class II and promiscuous recognition by T cells. Eur J Immunol 19: 2237–2242, 1989Google Scholar
  32. Pfeifer, J. D., Wick, M. J., Roberts, R. L., Findlay, K., Normark, S. J., and Harding, C. V. Phagocytic processing of bacterial antigens for class I MHC presentation to T cells. Nature 361: 359–362, 1993Google Scholar
  33. Rammensee, H.-G., Falk, K., and Rötzschke, O. Peptides naturally presented by MHC class I molecules. Annu Rev Immunol 11: 213–244, 1993Google Scholar
  34. Rudensky, A. Y., Preston-Hurlburt, P., Hong, S.-C., Barlow, A., and Janeway, C. A. Sequence analysis of peptides bound to MHC class II molecules. Nature 353: 622–627, 1991Google Scholar
  35. Rudensky, A. Y., Prestonhulburt, P., Alramadi, B. K., Rothbard, J., and Janeway, C. A. Truncation variants of peptides isolated from MHC class-II molecules suggest sequence motifs. Nature 359: 429–431, 1992Google Scholar
  36. Saper, M. A., Bjorkman, P. J., and Wiley, D. C. Refined structure of the human histocompatibility antigen HLA-A2 at 2.6A resolution. J Mol Biol 219: 277–319, 1991PubMedGoogle Scholar
  37. Schön, E., Born, I., Demuth, H. U., Faust, J., Neubert, K., Steinmetzer, T., Barth, A., and Ansorge, S. Dipeptidyl peptidase-IV in the immune system — effects of specific enzyme-inhibitors on activity of dipeptidyl peptidase-IV and proliferation of human lymphocytes. Biol Chem Hoppe Seyler 372: 305–311, 1991Google Scholar
  38. Sette, A., Buus, S., Appella, E., Adorino, L., and Grey, H. M. Structural requirements for the interaction between class II MHC molecules and peptide antigens. Immunol Res 9: 2–7, 1990Google Scholar
  39. Shimizu, Y., and DeMars, R. Production of human cells expressing individual transferred HLA-A, -B, -C genes using an HLA-A, -B,-C null human cell line. J Immunol 142: 3320–3328, 1989Google Scholar
  40. Shimizu, Y., Geraghty, D. E., Koller, B. H., Orr, H. T., and DeMars, R. Transfer and expression of three cloned human non-HLA-A, -B, C class I major histocompatibility complex genes in mutant lymphoblastoid cells. Proc Natl Acad Sci USA 85: 227–231, 1988Google Scholar
  41. Sinigaglia, F., Guttinger, M., Kilgus, J., Doran, D. M., Matile, H., Etlinger, H., Trzeciak, A., Gillessen, D., and Pink, J. R. L. A malaria T-cell epitope recognized in association with most mouse and human MHC class II molecules. Nature 336: 778–780, 1988Google Scholar
  42. Watson, A. J., DeMars, R., Trowbridge, I. S., Bach, F. H. Detection of a novel human class II HLA antigen. Nature 304: 358–361, 1983Google Scholar
  43. Zemmour, J., Little, A. M., Schendel, D. J., and Parham, P. The HLA-A,B negative mutant-cell line C1R expresses a novel HLA-B35 allele, which also has a point mutation in the translation initiation codon. J Immunol 148: 1941–1948, 1992Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • Kirsten Falk
    • 1
  • Olaf Rötzschke
    • 1
  • Stefan Stevanovíc
    • 2
  • Günther Jung
    • 2
  • Hans-Georg Rammensee
    • 1
  1. 1.Abteilung ImmungenetikMax-Planck-Institut für BiologieTübingenGermany
  2. 2.Institut für Organische ChemieUniversität TübingenTübingenGermany

Personalised recommendations