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. 1996 Aug 1;184(2):647–657. doi: 10.1084/jem.184.2.647

Identification of epitope mimics recognized by CTL reactive to the melanoma/melanocyte-derived peptide MART-1(27-35)

PMCID: PMC2192745  PMID: 8760818

Abstract

CTL reactivity to the epitope MART-1(27-35), of the melanoma (self) antigen MART-1/melan A is frequently observed in tumor-infiltrating lymphocytes and may be readily elicited from the peripheral blood of melanoma patients that express HLA-A*0201. Available data suggest that these observations contrast with those made for other HLA-A*0201- presented melanoma self antigens regarding the regularity of observed CTL responses. Based on preliminary findings, we hypothesized that the CTL response to MART-1 might be augmented in part by T cell encounters with peptides derived from sources other than MART-1, which show sequence similarity to MART-1(27-35). To test this idea, a protein database search for potential MART-1 epitope mimics was done using criteria developed from analyses of effector recognition of singly- substituted peptide analogues of MART-1(27-35). Synthetic peptides were made for a portion of the sequences retrieved; 12/40 peptides tested were able to sensitize target cells for lysis by one or more anti-MART- 1 effectors. The peptides recognized correspond to sequences occurring in a variety of proteins of viral, bacterial, and human (self) origin. One peptide derives from glycoprotein C of the common pathogen HSV-1; cells infected with recombinant vaccinia virus encoding native glycoprotein C were lysed by anti-MART-1 effectors. Our results overall indicate that sequences conforming to the A2.1 binding motif and possessing features essential to recognition by anti-MART-1 CTL occur frequently in proteins. These findings further suggest that T cells might encounter a variety of such sequences in vivo, and that epitope mimicry may play a role in modulating the CTL response to MART-1(27-35).

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Selected References

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  1. Bhardwaj V., Kumar V., Geysen H. M., Sercarz E. E. Degenerate recognition of a dissimilar antigenic peptide by myelin basic protein-reactive T cells. Implications for thymic education and autoimmunity. J Immunol. 1993 Nov 1;151(9):5000–5010. [PubMed] [Google Scholar]
  2. Boon T., Gajewski T. F., Coulie P. G. From defined human tumor antigens to effective immunization? Immunol Today. 1995 Jul;16(7):334–336. doi: 10.1016/0167-5699(95)80149-9. [DOI] [PubMed] [Google Scholar]
  3. Borysiewicz L. K., Sissons J. G. Cytotoxic T cells and human herpes virus infections. Curr Top Microbiol Immunol. 1994;189:123–150. doi: 10.1007/978-3-642-78530-6_8. [DOI] [PubMed] [Google Scholar]
  4. Boël P., Wildmann C., Sensi M. L., Brasseur R., Renauld J. C., Coulie P., Boon T., van der Bruggen P. BAGE: a new gene encoding an antigen recognized on human melanomas by cytolytic T lymphocytes. Immunity. 1995 Feb;2(2):167–175. doi: 10.1016/s1074-7613(95)80053-0. [DOI] [PubMed] [Google Scholar]
  5. Brichard V., Van Pel A., Wölfel T., Wölfel C., De Plaen E., Lethé B., Coulie P., Boon T. The tyrosinase gene codes for an antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med. 1993 Aug 1;178(2):489–495. doi: 10.1084/jem.178.2.489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cao W., Tykodi S. S., Esser M. T., Braciale V. L., Braciale T. J. Partial activation of CD8+ T cells by a self-derived peptide. Nature. 1995 Nov 16;378(6554):295–298. doi: 10.1038/378295a0. [DOI] [PubMed] [Google Scholar]
  7. Cole D. J., Weil D. P., Shamamian P., Rivoltini L., Kawakami Y., Topalian S., Jennings C., Eliyahu S., Rosenberg S. A., Nishimura M. I. Identification of MART-1-specific T-cell receptors: T cells utilizing distinct T-cell receptor variable and joining regions recognize the same tumor epitope. Cancer Res. 1994 Oct 15;54(20):5265–5268. [PubMed] [Google Scholar]
  8. Coulie P. G., Brichard V., Van Pel A., Wölfel T., Schneider J., Traversari C., Mattei S., De Plaen E., Lurquin C., Szikora J. P. A new gene coding for a differentiation antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med. 1994 Jul 1;180(1):35–42. doi: 10.1084/jem.180.1.35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Coulie P. G., Lehmann F., Lethé B., Herman J., Lurquin C., Andrawiss M., Boon T. A mutated intron sequence codes for an antigenic peptide recognized by cytolytic T lymphocytes on a human melanoma. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7976–7980. doi: 10.1073/pnas.92.17.7976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cox A. L., Skipper J., Chen Y., Henderson R. A., Darrow T. L., Shabanowitz J., Engelhard V. H., Hunt D. F., Slingluff C. L., Jr Identification of a peptide recognized by five melanoma-specific human cytotoxic T cell lines. Science. 1994 Apr 29;264(5159):716–719. doi: 10.1126/science.7513441. [DOI] [PubMed] [Google Scholar]
  11. Dellabona P., Casorati G., Friedli B., Angman L., Sallusto F., Tunnacliffe A., Roosneek E., Lanzavecchia A. In vivo persistence of expanded clones specific for bacterial antigens within the human T cell receptor alpha/beta CD4-8- subset. J Exp Med. 1993 Jun 1;177(6):1763–1771. doi: 10.1084/jem.177.6.1763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dunkley M., Pabst R., Cripps A. An important role for intestinally derived T cells in respiratory defence. Immunol Today. 1995 May;16(5):231–236. doi: 10.1016/0167-5699(95)80165-0. [DOI] [PubMed] [Google Scholar]
  13. Ferrone S., Marincola F. M. Loss of HLA class I antigens by melanoma cells: molecular mechanisms, functional significance and clinical relevance. Immunol Today. 1995 Oct;16(10):487–494. doi: 10.1016/0167-5699(95)80033-6. [DOI] [PubMed] [Google Scholar]
  14. Garza K. M., Tung K. S. Frequency of molecular mimicry among T cell peptides as the basis for autoimmune disease and autoantibody induction. J Immunol. 1995 Dec 1;155(11):5444–5448. [PubMed] [Google Scholar]
  15. Genevée C., Diu A., Nierat J., Caignard A., Dietrich P. Y., Ferradini L., Roman-Roman S., Triebel F., Hercend T. An experimentally validated panel of subfamily-specific oligonucleotide primers (V alpha 1-w29/V beta 1-w24) for the study of human T cell receptor variable V gene segment usage by polymerase chain reaction. Eur J Immunol. 1992 May;22(5):1261–1269. doi: 10.1002/eji.1830220522. [DOI] [PubMed] [Google Scholar]
  16. Jameson S. C., Hogquist K. A., Bevan M. J. Specificity and flexibility in thymic selection. Nature. 1994 Jun 30;369(6483):750–752. doi: 10.1038/369750a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kast W. M., Brandt R. M., Sidney J., Drijfhout J. W., Kubo R. T., Grey H. M., Melief C. J., Sette A. Role of HLA-A motifs in identification of potential CTL epitopes in human papillomavirus type 16 E6 and E7 proteins. J Immunol. 1994 Apr 15;152(8):3904–3912. [PubMed] [Google Scholar]
  18. Kawakami Y., Eliyahu S., Delgado C. H., Robbins P. F., Rivoltini L., Topalian S. L., Miki T., Rosenberg S. A. Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3515–3519. doi: 10.1073/pnas.91.9.3515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kawakami Y., Eliyahu S., Delgado C. H., Robbins P. F., Sakaguchi K., Appella E., Yannelli J. R., Adema G. J., Miki T., Rosenberg S. A. Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6458–6462. doi: 10.1073/pnas.91.14.6458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kawakami Y., Eliyahu S., Sakaguchi K., Robbins P. F., Rivoltini L., Yannelli J. R., Appella E., Rosenberg S. A. Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2-restricted tumor infiltrating lymphocytes. J Exp Med. 1994 Jul 1;180(1):347–352. doi: 10.1084/jem.180.1.347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lehmann F., Marchand M., Hainaut P., Pouillart P., Sastre X., Ikeda H., Boon T., Coulie P. G. Differences in the antigens recognized by cytolytic T cells on two successive metastases of a melanoma patient are consistent with immune selection. Eur J Immunol. 1995 Feb;25(2):340–347. doi: 10.1002/eji.1830250206. [DOI] [PubMed] [Google Scholar]
  22. Ljunggren H. G., Stam N. J., Ohlén C., Neefjes J. J., Höglund P., Heemels M. T., Bastin J., Schumacher T. N., Townsend A., Kärre K. Empty MHC class I molecules come out in the cold. Nature. 1990 Aug 2;346(6283):476–480. doi: 10.1038/346476a0. [DOI] [PubMed] [Google Scholar]
  23. Madden D. R., Garboczi D. N., Wiley D. C. The antigenic identity of peptide-MHC complexes: a comparison of the conformations of five viral peptides presented by HLA-A2. Cell. 1993 Nov 19;75(4):693–708. doi: 10.1016/0092-8674(93)90490-h. [DOI] [PubMed] [Google Scholar]
  24. Marincola F. M., Venzon D., White D., Rubin J. T., Lotze M. T., Simonis T. B., Balkissoon J., Rosenberg S. A., Parkinson D. R. HLA association with response and toxicity in melanoma patients treated with interleukin 2-based immunotherapy. Cancer Res. 1992 Dec 1;52(23):6561–6566. [PubMed] [Google Scholar]
  25. Marrack P., McCormack J., Kappler J. Presentation of antigen, foreign major histocompatibility complex proteins and self by thymus cortical epithelium. Nature. 1989 Apr 6;338(6215):503–505. doi: 10.1038/338503a0. [DOI] [PubMed] [Google Scholar]
  26. Martin S., Mercadal C. M., Weir J. P., Rouse B. T. The proportion of herpes simplex virus-specific cytotoxic T lymphocytes (Tc) that recognize glycoprotein C varies between individual mice and is dependent on the form of immunization. Viral Immunol. 1993 Spring;6(1):21–33. doi: 10.1089/vim.1993.6.21. [DOI] [PubMed] [Google Scholar]
  27. Ohashi P. S., Oehen S., Buerki K., Pircher H., Ohashi C. T., Odermatt B., Malissen B., Zinkernagel R. M., Hengartner H. Ablation of "tolerance" and induction of diabetes by virus infection in viral antigen transgenic mice. Cell. 1991 Apr 19;65(2):305–317. doi: 10.1016/0092-8674(91)90164-t. [DOI] [PubMed] [Google Scholar]
  28. Oldstone M. B. Molecular mimicry and autoimmune disease. Cell. 1987 Sep 11;50(6):819–820. doi: 10.1016/0092-8674(87)90507-1. [DOI] [PubMed] [Google Scholar]
  29. Pearson W. R., Lipman D. J. Improved tools for biological sequence comparison. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2444–2448. doi: 10.1073/pnas.85.8.2444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Quaratino S., Thorpe C. J., Travers P. J., Londei M. Similar antigenic surfaces, rather than sequence homology, dictate T-cell epitope molecular mimicry. Proc Natl Acad Sci U S A. 1995 Oct 24;92(22):10398–10402. doi: 10.1073/pnas.92.22.10398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Rivoltini L., Kawakami Y., Sakaguchi K., Southwood S., Sette A., Robbins P. F., Marincola F. M., Salgaller M. L., Yannelli J. R., Appella E. Induction of tumor-reactive CTL from peripheral blood and tumor-infiltrating lymphocytes of melanoma patients by in vitro stimulation with an immunodominant peptide of the human melanoma antigen MART-1. J Immunol. 1995 Mar 1;154(5):2257–2265. [PubMed] [Google Scholar]
  32. Robbins P. F., El-Gamil M., Li Y. F., Kawakami Y., Loftus D., Appella E., Rosenberg S. A. A mutated beta-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes. J Exp Med. 1996 Mar 1;183(3):1185–1192. doi: 10.1084/jem.183.3.1185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Salgaller M. L., Afshar A., Marincola F. M., Rivoltini L., Kawakami Y., Rosenberg S. A. Recognition of multiple epitopes in the human melanoma antigen gp100 by peripheral blood lymphocytes stimulated in vitro with synthetic peptides. Cancer Res. 1995 Nov 1;55(21):4972–4979. [PubMed] [Google Scholar]
  34. Salvi S., Segalla F., Rao S., Arienti F., Sartori M., Bratina G., Caronni E., Anichini A., Clemente C., Parmiani G. Overexpression of the T-cell receptor beta-chain variable region TCRBV14 in HLA-A2-matched primary human melanomas. Cancer Res. 1995 Aug 1;55(15):3374–3379. [PubMed] [Google Scholar]
  35. Schwartz R. H. A cell culture model for T lymphocyte clonal anergy. Science. 1990 Jun 15;248(4961):1349–1356. doi: 10.1126/science.2113314. [DOI] [PubMed] [Google Scholar]
  36. Sensi M., Parmiani G. Analysis of TCR usage in human tumors: a new tool for assessing tumor-specific immune responses. Immunol Today. 1995 Dec;16(12):588–595. doi: 10.1016/0167-5699(95)80082-4. [DOI] [PubMed] [Google Scholar]
  37. Sensi M., Traversari C., Radrizzani M., Salvi S., Maccalli C., Mortarini R., Rivoltini L., Farina C., Nicolini G., Wölfel T. Cytotoxic T-lymphocyte clones from different patients display limited T-cell-receptor variable-region gene usage in HLA-A2-restricted recognition of the melanoma antigen Melan-A/MART-1. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5674–5678. doi: 10.1073/pnas.92.12.5674. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Sette A., Alexander J., Ruppert J., Snoke K., Franco A., Ishioka G., Grey H. M. Antigen analogs/MHC complexes as specific T cell receptor antagonists. Annu Rev Immunol. 1994;12:413–431. doi: 10.1146/annurev.iy.12.040194.002213. [DOI] [PubMed] [Google Scholar]
  39. Shimoda S., Nakamura M., Ishibashi H., Hayashida K., Niho Y. HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases. J Exp Med. 1995 May 1;181(5):1835–1845. doi: 10.1084/jem.181.5.1835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Smith G. L., Levin J. Z., Palese P., Moss B. Synthesis and cellular location of the ten influenza polypeptides individually expressed by recombinant vaccinia viruses. Virology. 1987 Oct;160(2):336–345. doi: 10.1016/0042-6822(87)90004-3. [DOI] [PubMed] [Google Scholar]
  41. Spagnoli G. C., Schaefer C., Willimann T. E., Kocher T., Amoroso A., Juretic A., Zuber M., Luscher U., Harder F., Heberer M. Peptide-specific CTL in tumor infiltrating lymphocytes from metastatic melanomas expressing MART-1/Melan-A, gp100 and Tyrosinase genes: a study in an unselected group of HLA-A2.1-positive patients. Int J Cancer. 1995 Oct 20;64(5):309–315. doi: 10.1002/ijc.2910640505. [DOI] [PubMed] [Google Scholar]
  42. 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]
  43. Stevens E. J., Jacknin L., Robbins P. F., Kawakami Y., el Gamil M., Rosenberg S. A., Yannelli J. R. Generation of tumor-specific CTLs from melanoma patients by using peripheral blood stimulated with allogeneic melanoma tumor cell lines. Fine specificity and MART-1 melanoma antigen recognition. J Immunol. 1995 Jan 15;154(2):762–771. [PubMed] [Google Scholar]
  44. Sztein M. B., Tanner M. K., Polotsky Y., Orenstein J. M., Levine M. M. Cytotoxic T lymphocytes after oral immunization with attenuated vaccine strains of Salmonella typhi in humans. J Immunol. 1995 Oct 15;155(8):3987–3993. [PubMed] [Google Scholar]
  45. Van den Eynde B., Peeters O., De Backer O., Gaugler B., Lucas S., Boon T. A new family of genes coding for an antigen recognized by autologous cytolytic T lymphocytes on a human melanoma. J Exp Med. 1995 Sep 1;182(3):689–698. doi: 10.1084/jem.182.3.689. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Wang R. F., Robbins P. F., Kawakami Y., Kang X. Q., Rosenberg S. A. Identification of a gene encoding a melanoma tumor antigen recognized by HLA-A31-restricted tumor-infiltrating lymphocytes. J Exp Med. 1995 Feb 1;181(2):799–804. doi: 10.1084/jem.181.2.799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Wei S., Charmley P., Robinson M. A., Concannon P. The extent of the human germline T-cell receptor V beta gene segment repertoire. Immunogenetics. 1994;40(1):27–36. doi: 10.1007/BF00163961. [DOI] [PubMed] [Google Scholar]
  48. Weir J. P., Bennett M., Allen E. M., Elkins K. L., Martin S., Rouse B. T. Recombinant vaccinia virus expressing the herpes simplex virus type 1 glycoprotein C protects mice against herpes simplex virus challenge. J Gen Virol. 1989 Oct;70(Pt 10):2587–2594. doi: 10.1099/0022-1317-70-10-2587. [DOI] [PubMed] [Google Scholar]
  49. Wucherpfennig K. W., Strominger J. L. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell. 1995 Mar 10;80(5):695–705. doi: 10.1016/0092-8674(95)90348-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Wölfel T., Hauer M., Schneider J., Serrano M., Wölfel C., Klehmann-Hieb E., De Plaen E., Hankeln T., Meyer zum Büschenfelde K. H., Beach D. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science. 1995 Sep 1;269(5228):1281–1284. doi: 10.1126/science.7652577. [DOI] [PubMed] [Google Scholar]
  51. Zuckermann F. A., Zsak L., Mettenleiter T. C., Ben-Porat T. Pseudorabies virus glycoprotein gIII is a major target antigen for murine and swine virus-specific cytotoxic T lymphocytes. J Virol. 1990 Feb;64(2):802–812. doi: 10.1128/jvi.64.2.802-812.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. van der Bruggen P., Traversari C., Chomez P., Lurquin C., De Plaen E., Van den Eynde B., Knuth A., Boon T. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science. 1991 Dec 13;254(5038):1643–1647. doi: 10.1126/science.1840703. [DOI] [PubMed] [Google Scholar]

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