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Classification of A1- and A24-supertype molecules by analysis of their MHC-peptide binding repertoires

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Abstract

At the functional level, the majority of human leukocyte antigen (HLA) class I MHC variants can be classified into about ten different major groups, or supertypes, characterized by overlapping peptide binding motifs and repertoires. Previous studies have detailed the peptide binding specificity of the HLA A2, A3, B7, and B44 supertypes, and predicted, on the basis of MHC pocket structures, known motifs, or the sequence of T cell epitopes, the existence of the HLA A1 and A24 supertypes. Direct experimental validation of the A1 and A24 supertypes, however, has been lacking. In the current study, the peptide-binding repertoires and main anchor specificities of several common HLA A molecules (A*0101, A*2301, A*2402, A*2601, A*2902, and A*3002) predicted to be members of the A1 or A24 supertypes were analyzed and defined using single amino acid substituted peptides and a large peptide library. Based on the present findings, the A1 supertype includes A*0101, A*2601, A*2902, and A*3002, whereas the A24 supertype includes A*2301 and A*2402. Interestingly, A*2902 is associated with a motif and peptide binding repertoire that overlaps significantly with those of all of the A1- and A24-supertype molecules studied, representing—to our knowledge—the first report of significant cross-reactivity among molecules belonging to different supertypes.

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References

  • Allen TM, Sidney J, del Guercio MF, Glickman RL, Lensmeyer GL, Wiebe DA, DeMars R, Pauza CD, Johnson RP, Sette A, Watkins DI (1998) Characterization of the peptide binding motif of a rhesus MHC class I molecule (Mamu-A*01) that binds an immunodominant CTL epitope from simian immunodeficiency virus. J Immunol 160:6062–6071

    PubMed  CAS  Google Scholar 

  • Altfeld MA, Livingston B, Reshamwala N, Nguyen PT, Addo MM, Shea A, Newman M, Fikes J, Sidney J, Wentworth P, Chesnut R, Eldridge RL, Rosenberg ES, Robbins GK, Brander C, Sax PE, Boswell S, Flynn T, Buchbinder S, Goulder PJ, Walker BD, Sette A, Kalams SA (2001) Identification of novel HLA-A2-restricted human immunodeficiency virus type 1-specific cytotoxic T-lymphocyte epitopes predicted by the HLA-A2 supertype peptide-binding motif. J Virol 75:1301–1311

    Article  PubMed  CAS  Google Scholar 

  • Bertoni R, Sidney J, Fowler P, Chesnut RW, Chisari FV, Sette A (1997) Human histocompatibility leukocyte antigen-binding supermotifs predict broadly cross-reactive cytotoxic T lymphocyte responses in patients with acute hepatitis. J Clin Invest 100:503–513

    Article  PubMed  CAS  Google Scholar 

  • Boisgerault F, Khalil I, Tieng V, Connan F, Tabary T, Cohen JH, Choppin J, Charron D, Toubert A (1996) Definition of the HLA-A29 peptide ligand motif allows prediction of potential T-cell epitopes from the retinal soluble antigen, a candidate autoantigen in birdshot retinopathy. Proc Natl Acad Sci U S A 93:3466–3470

    Article  PubMed  CAS  Google Scholar 

  • Burrows SR, Elkington RA, Miles JJ, Green KJ, Walker S, Haryana SM, Moss DJ, Dunckley H, Burrows JM, Khanna R (2003) Promiscuous CTL recognition of viral epitopes on multiple human leukocyte antigens: biological validation of the proposed HLA A24 supertype. J Immunol 171:1407–1412

    PubMed  CAS  Google Scholar 

  • Chang KM, Gruener NH, Southwood S, Sidney J, Pape GR, Chisari FV, Sette A (1999) Identification of HLA-A3 and -B7-restricted CTL response to hepatitis C virus in patients with acute and chronic hepatitis C. J Immunol 162:1156–1164

    PubMed  CAS  Google Scholar 

  • del Guercio MF, Sidney J, Hermanson G, Perez C, Grey HM, Kubo RT, Sette A (1995) Binding of a peptide antigen to multiple HLA alleles allows definition of an A2-like supertype. J Immunol 154:685–693

    PubMed  Google Scholar 

  • Doolan DL, Hoffman SL, Southwood S, Wentworth PA, Sidney J, Chesnut RW, Keogh E, Appella E, Nutman TB, Lal AA, Gordon DM, Oloo A, Sette A (1997) Degenerate cytotoxic T cell epitopes from P. falciparum restricted by multiple HLA-A and HLA-B supertype alleles. Immunity 7:97–112

    Article  PubMed  CAS  Google Scholar 

  • Doytchinova IA, Guan P, Flower DR (2004) Identifiying human MHC supertypes using bioinformatic methods. J Immunol 172:4314–4323

    PubMed  CAS  Google Scholar 

  • Drouet M, Aussel L, Drenou B, Fauchet R (1995) Quantification and molecular analysis of plasmatic HLA-BCw molecules with a locus B and Cw HLA specific mAb (B1.23.2 mAb). Eur J Immunogenet 22:363–370

    Article  PubMed  CAS  Google Scholar 

  • Dumrese T, Stevanovic S, Seeger FH, Yamada N, Ishikawa Y, Tokunaga K, Takiguchi M, Rammensee H (1998) HLA-A26 subtype A pockets accommodate acidic N-termini of ligands. Immunogenetics 48:350–353

    Article  PubMed  CAS  Google Scholar 

  • Falk K, Rotzschke O, Takiguchi M, Gnau V, Stevanovic S, Jung G, Rammensee HG (1995) Peptide motifs of HLA-B58, B60, B61, and B62 molecules. Immunogenetics 41:165–168

    Article  PubMed  CAS  Google Scholar 

  • Fleischhauer K, Tanzarella S, Wallny HJ, Bordignon C, Traversari C (1996) Multiple HLA-A alleles can present an immunodominant peptide of the human melanoma antigen Melan-A/MART-1 to a peptide-specific HLA-A*0201+ cytotoxic T cell line. J Immunol 157:787–797

    PubMed  CAS  Google Scholar 

  • Gjertson DW, Lee S-H (1998) HLA-A/B and -DRB1/DQB1 allele-level haplotype frequencies. In: Gjertson DW, Terasaki PI (eds) HLA 1998. American Society for Histocompatibility and Immunogenetics, Lenexa, KS, USA, pp 365–450

    Google Scholar 

  • Gulukota K, Sidney J, Sette A, DeLisi C (1997) Two complementary methods for predicting peptides binding major histocompatibility complex molecules. J Mol Biol 267:1258–1267

    Article  PubMed  CAS  Google Scholar 

  • Harris PE, Colovai A, Liu Z, Dalla Favera R, Suciu-Foca N (1993) Naturally processed HLA class I bound peptides from c-myc-transfected cells reveal allele-specific motifs. J Immunol 151:5966–5974

    PubMed  CAS  Google Scholar 

  • Imanishi T, Akaza T, Kimura A, Tokunaga K, Gojoubori T (1992) Allele and haplotype frequencies for HLA and complement loci in various ethnic groups. In Tsuji K, Aizaqa M, Sasazuki T (eds) HLA 1991: Proceedings of the Eleventh International Histocompatibility Workshop and Conference. Oxford University Press, Oxford, pp 1065–1220

    Google Scholar 

  • Kast WM, Brandt RM, Sidney J, Drijfhout JW, Kubo RT, Grey HM, Melief CJ, Sette A (1994) Role of HLA-A motifs in identification of potential CTL epitopes in human papillomavirus type 16 E6 and E7 proteins. J Immunol 152:3904–3912

    PubMed  CAS  Google Scholar 

  • Kato K, Trapani JA, Allopenna J, Dupont B, Yang SY (1989) Molecular analysis of the serologically defined HLA-Aw19 antigens. A genetically distinct family of HLA-A antigens comprising A29, A31, A32, and Aw33, but probably not A30. J Immunol 143:3371–3378

    PubMed  CAS  Google Scholar 

  • Kawashima I, Hudson SJ, Tsai V, Southwood S, Takesako K, Appella E, Sette A, Celis E (1998) The multi-epitope approach for immunotherapy for cancer: identification of several CTL epitopes from various tumor-associated antigens expressed on solid epithelial tumors. Hum Immunol 59:1–14

    Article  PubMed  CAS  Google Scholar 

  • Khanna R, Burrows SR, Nicholls J, Poulsen LM (1998) Identification of cytotoxic T cell epitopes within Epstein–Barr virus (EBV) oncogene latent membrane protein 1 (LMP1): evidence for HLA A2 supertype-restricted immune recognition of EBV-infected cells by LMP1-specific cytotoxic T lymphocytes. Eur J Immunol 28:451–458

    Article  PubMed  CAS  Google Scholar 

  • Kondo A, Sidney J, Southwood S, del Guercio MF, Appella E, Sakamoto H, Celis E, Grey HM, Chesnut RW, Kubo RT et al (1995) Prominent roles of secondary anchor residues in peptide binding to HLA-A24 human class I molecules. J Immunol 155:4307–4312

    PubMed  CAS  Google Scholar 

  • Kondo A, Sidney J, Southwood S, del Guercio MF, Appella E, Sakamoto H, Grey HM, Celis E, Chesnut RW, Kubo RT, Sette A (1997) Two distinct HLA-A*0101-specific submotifs illustrate alternative peptide binding modes. Immunogenetics 45:249–258

    Article  PubMed  CAS  Google Scholar 

  • Krausa P, Munz C, Keilholz W, Stevanovic S, Jones EY, Browning M, Bunce M, Rammensee HG, McMichael A (2000) Definition of peptide binding motifs amongst the HLA-A*30 allelic group. Tissue Antigens 56:10–18

    Article  PubMed  CAS  Google Scholar 

  • Kubo RT, Sette A, Grey HM, Appella E, Sakaguchi K, Zhu NZ, Arnott D, Sherman N, Shabanowitz J, Michel H et al (1994) Definition of specific peptide motifs for four major HLA-A alleles. J Immunol 152:3913–3924

    PubMed  CAS  Google Scholar 

  • Livingston BD, Crimi C, Fikes J, Chesnut RW, Sidney J, Sette A (1999) Immunization with the HBV core 18–27 epitope elicits CTL responses in humans expressing different HLA-A2 supertype molecules. Hum Immunol 60:1013–1017

    Article  PubMed  CAS  Google Scholar 

  • Luescher IF, Romero P, Kuznetsov D, Rimoldi D, Coulie P, Cerottini JC, Jongeneel CV (1996) HLA photoaffinity labeling reveals overlapping binding of homologous melanoma-associated gene peptides by HLA-A1, HLA-A29, and HLA-B44. J Biol Chem 271:12463–12471

    Article  PubMed  CAS  Google Scholar 

  • Lund O, Nielsen M, Kesmir C, Petersen AG, Lundegaard C, Worning P, Sylvester-Hvid C, Lamberth K, Roder G, Justesen S, Buus S, Brunak S (2004) Definition of supertypes for HLA molecules using clustering of specificity matrices. Immunogenetics 55:797–810

    Article  PubMed  CAS  Google Scholar 

  • Marsh SG, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA, Geraghty DE, Hansen JA, Mach B, Mayr WR, Parham P, Petersdorf EW, Sasazuki T, Schreuder GM, Strominger JL, Svejgaard A, Terasaki PI (2002) Nomenclature for factors of the HLA system, 2002. Hum Immunol 63:1213–1268

    Article  PubMed  CAS  Google Scholar 

  • Mothe BR, Sidney J, Dzuris JL, Liebl ME, Fuenger S, Watkins DI, Sette A (2002) Characterization of the peptide-binding specificity of Mamu-B*17 and identification of Mamu-B*17-restricted epitopes derived from simian immunodeficiency virus proteins. J Immunol 169:210–219

    PubMed  CAS  Google Scholar 

  • Nussenblatt RB, Mittal KK, Ryan S, Green WR, Maumenee AE (1982) Birdshot retinochoroidopathy associated with HLA-A29 antigen and immune responsiveness to retinal S-antigen. Am J Ophthalmol 94:147–158

    PubMed  CAS  Google Scholar 

  • Priem HA, Kijlstra A, Noens L, Baarsma GS, De Laey JJ, Oosterhuis JA (1988) HLA typing in birdshot chorioretinopathy. Am J Ophthalmol 105:182–185

    PubMed  CAS  Google Scholar 

  • Rebai N, Malissen B (1983) Structural and genetic analyses of HLA class I molecules using monoclonal xenoantibodies. Tissue Antigens 22:107–117

    Article  PubMed  CAS  Google Scholar 

  • Rivoltini L, Loftus DJ, Barracchini K, Arienti F, Mazzocchi A, Biddison WE, Salgaller ML, Appella E, Parmiani G, Marincola FM (1996) Binding and presentation of peptides derived from melanoma antigens MART-1 and glycoprotein-100 by HLA-A2 subtypes. Implications for peptide-based immunotherapy. J Immunol 156:3882–3891

    PubMed  CAS  Google Scholar 

  • Ruppert J, Sidney J, Celis E, Kubo RT, Grey HM, Sette A (1993) Prominent role of secondary anchor residues in peptide binding to HLA-A2.1 molecules. Cell 74:929–937

    Article  PubMed  CAS  Google Scholar 

  • Sette A, Sidney J (1998) HLA supertypes and supermotifs: a functional perspective on HLA polymorphism. Curr Opin Immunol 10:478–482

    Article  PubMed  CAS  Google Scholar 

  • Sette A, Sidney J (1999) Nine major HLA class I supertypes account for the vast preponderance of HLA-A and -B polymorphism. Immunogenetics 50:201–212

    Article  PubMed  CAS  Google Scholar 

  • Sette A, Vitiello A, Reherman B, Fowler P, Nayersina R, Kast WM, Melief CJ, Oseroff C, Yuan L, Ruppert J et al (1994) The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes. J Immunol 153:5586–5592

    PubMed  CAS  Google Scholar 

  • Sette A, Sidney J, Livingston B, Dzuris J, Crimi C, Walker CM, Southwood S, Collins EJ, Hughes A (2003) Class I molecules with similar peptide binding specificities are the result of both common ancestry and convergent evolution. Immunogenetics 54:830–841

    Google Scholar 

  • Sidney J, del Guercio MF, Southwood S, Engelhard VH, Appella E, Rammensee HG, Falk K, Rotzschke O, Takiguchi M, Kubo RT et al (1995) Several HLA alleles share overlapping peptide specificities. J Immunol 154:247–259

    PubMed  CAS  Google Scholar 

  • Sidney J, Grey HM, Kubo RT, Sette A (1996a) Practical, biochemical and evolutionary implications of the discovery of HLA class I supermotifs. Immunol Today 17:261–266

    Article  PubMed  CAS  Google Scholar 

  • Sidney J, Grey HM, Southwood S, Celis E, Wentworth PA, del Guercio MF, Kubo RT, Chesnut RW, Sette A (1996b) Definition of an HLA-A3-like supermotif demonstrates the overlapping peptide-binding repertoires of common HLA molecules. Hum Immunol 45:79–93

    Article  PubMed  CAS  Google Scholar 

  • Sidney J, Southwood S, del Guercio MF, Grey HM, Chesnut RW, Kubo RT, Sette, A (1996c) Specificity and degeneracy in peptide binding to HLA-B7-like class I molecules. J Immunol 157:3480–3490

    PubMed  CAS  Google Scholar 

  • Sidney J, del Guercio MF, Southwood S, Hermanson G, Maewal A, Appella E, Sette A (1997) The HLA-A*0207 peptide binding repertoire is limited to a subset of the A*0201 repertoire. Hum Immunol 58:12–20

    Article  PubMed  CAS  Google Scholar 

  • Sidney J, Southwood S, Oseroff C, Del Guercio MF, Sette A, Grey H (1998) Measurement of MHC/peptide interactions by gel filtration. In: Current protocols in immunology. Wiley, New York, pp 18.3.1–18.3.19

    Google Scholar 

  • Sidney J, Dzuris JL, Newman MJ, Johnson RP, Kaur A, Amitinder K, Walker CM, Appella E, Mothe B, Watkins DI, Sette A (2000) Definition of the Mamu A*01 peptide binding specificity: application to the identification of wild-type and optimized ligands from simian immunodeficiency virus regulatory proteins. J Immunol 165:6387–6399

    PubMed  CAS  Google Scholar 

  • Sidney J, Southwood S, Mann DL, Fernandez-Vina MA, Newman MJ, Sette A (2001) Majority of peptides binding HLA-A*0201 with high affinity crossreact with other A2-supertype molecules. Hum Immunol 62:1200–1216

    Article  PubMed  CAS  Google Scholar 

  • Sidney J, Southwood S, Pasquetto V, Sette A (2003) Simultaneous prediction of binding capacity for multiple molecules of the HLA B44-supertype. J Immunol 171:5964–5974

    PubMed  CAS  Google Scholar 

  • Southwood S, Sidney J, Kondo A, del Guercio MF, Appella E, Hoffman S, Kubo RT, Chesnut RW, Grey HM, Sette A (1998) Several common HLA-DR types share largely overlapping peptide binding repertoires. J Immunol 160:3363–3373

    PubMed  CAS  Google Scholar 

  • Sterkers G, Henin Y, Kalil J, Bagot M, Levy JP (1983) Influence of HLA class I- and class II-specific monoclonal antibodies on DR-restricted lymphoproliferative responses. I. Unseparated populations of effector cells. J Immunol 131:2735–2740

    PubMed  CAS  Google Scholar 

  • Threlkeld SC, Wentworth PA, Kalams SA, Wilkes BM, Ruhl DJ, Keogh E, Sidney J, Southwood S, Walker BD, Sette A (1997) Degenerate and promiscuous recognition by CTL of peptides presented by the MHC class I A3-like superfamily: implications for vaccine development. J Immunol 159:1648–1657

    PubMed  CAS  Google Scholar 

  • Trapani JA, Mizuno S, Kang SH, Yang SY, Dupont B (1989) Molecular mapping of a new public HLA class I epitope shared by all HLA-B and HLA-C antigens and defined by a monoclonal antibody. Immunogenetics 29:25–32

    Article  PubMed  CAS  Google Scholar 

  • Wang RF, Johnston SL, Southwood S, Sette A, Rosenberg SA (1998) Recognition of an antigenic peptide derived from tyrosinase-related protein-2 by CTL in the context of HLA-A31 and -A33. J Immunol 160:890–897

    PubMed  CAS  Google Scholar 

  • Zinszner H, Masset M, Bourge JF, Colombani J, Cohen D, Degos L, Paul P (1990) Nucleotide sequence of the HLA-A26 class I gene: identification of specific residues and molecular mapping of public HLA class I epitopes. Hum Immunol 27:155–166

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We would like to thank Kris Haynes, Timothy J. Pencille, and Mary Wittig for their expert technical assistance, and Drs. Howard M. Grey and Bjoern Peters for their helpful discussions. This work is supported by NIH NIAID contracts N01-AI-40023, N01-AI-40024, and HHSN266200400006C, and all experiments comply with current USA laws.

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  1. La Jolla Institute for Allergy and Immunology, 3030 Bunker Hill St., Ste. 326, San Diego, CA, 92109, USA

    John Sidney & Alessandro Sette

  2. Epimmune Inc., 5820 Nancy Ridge Rd., San Diego, CA, 92121, USA

    Scott Southwood

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  1. John Sidney
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Correspondence to Alessandro Sette.

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Sidney, J., Southwood, S. & Sette, A. Classification of A1- and A24-supertype molecules by analysis of their MHC-peptide binding repertoires. Immunogenetics 57, 393–408 (2005). https://doi.org/10.1007/s00251-005-0004-2

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