1887

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Volume 88, Issue 3

Full-length EBNA1 mRNA-transduced dendritic cells stimulate cytotoxic T lymphocytes recognizing a novel HLA-Cw*0303- and -Cw*0304-restricted epitope on EBNA1-expressing cells Free

Abstract

Epstein–Barr virus (EBV)-encoded nuclear antigen 1 (EBNA1) is an attractive target for immunotherapy against EBV-associated malignancies because it is expressed in all EBV-positive cells. Although CD8 cytotoxic T-lymphocyte (CTL) epitope presentation is largely prevented by its glycine–alanine-repeat domain (GAr), the use of mRNA-transduced dendritic cells (DCs) would offer the advantage of priming EBNA1-specific CTLs. After stimulation with GAr-containing EBNA1-transduced monocyte-derived DCs, two EBNA1-specific CTL clones, B5 and C6, were isolated successfully from a healthy donor. These CTLs recognize peptides in the context of HLA-B*3501 and HLA-Cw*0303, respectively. A novel epitope, FVYGGSKTSL, was then identified, presented by both HLA-Cw*0303 and -Cw*0304, which are expressed by >35 % of Japanese, >20 % of Northern Han Chinese and >25 % of Caucasians. The mixed lymphocyte–peptide culture method revealed that FVYGGSKTSL-specific CTL-precursor frequencies in HLA-Cw*0303- or -Cw*0304-positive donors were between 1×10 and 1×10 CD8 T cells. Moreover, both CTL clones inhibited growth of HLA-matched EBV-transformed B lymphocytes , and B5 CTLs produced a gamma interferon response to EBNA1-expressing gastric carcinoma cells in the context of HLA-Cw*0303. These data demonstrate that EBNA1 mRNA-transduced DCs may be useful tools for inducing EBNA1-specific CTLs that might be of clinical interest for CTL therapy of EBV-associated malignancies.

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2007-03-01
2024-04-20
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References

  1. Akatsuka Y., Goldberg T. A., Kondo E., Martin E. G., Obata Y., Morishima Y., Takahashi T., Hansen J. A. 2002; Efficient cloning and expression of HLA class I cDNA in human B-lymphoblastoid cell lines. Tissue Antigens 59:502–511 [CrossRef]
     [Google Scholar]
  2. Babcock G. J., Hochberg D., Thorley-Lawson A. D. 2000; The expression pattern of Epstein-Barr virus latent genes in vivo is dependent upon the differentiation stage of the infected B cell. Immunity 13:497–506 [CrossRef]
     [Google Scholar]
  3. Bai Y., Soda Y., Izawa K., Tanabe T., Kang X., Tojo A., Hoshino H., Miyoshi H., Asano S., Tani K. 2003; Effective transduction and stable transgene expression in human blood cells by a third-generation lentiviral vector. Gene Ther 10:1446–1457 [CrossRef]
     [Google Scholar]
  4. Bickham K., Munz C., Tsang M. L., Larsson M., Fonteneau J. F., Bhardwaj N., Steinman R. 2001; EBNA1-specific CD4+ T cells in healthy carriers of Epstein-Barr virus are primarily Th1 in function. J Clin Invest 107:121–130 [CrossRef]
     [Google Scholar]
  5. Blake N., Lee S., Redchenko I., Thomas W., Steven N., Leese A., Steigerwald-Mullen P., Kurilla M. G., Frappier L., Rickinson A. 1997; Human CD8+ T cell responses to EBV EBNA1: HLA class I presentation of the (Gly-Ala)-containing protein requires exogenous processing. Immunity 7:791–802 [CrossRef]
     [Google Scholar]
  6. Blake N., Haigh T., Shaka'a G., Croom-Carter D., Rickinson A. 2000; The importance of exogenous antigen in priming the human CD8+ T cell response: lessons from the EBV nuclear antigen EBNA1. J Immunol 165:7078–7087 [CrossRef]
     [Google Scholar]
  7. Bollard C. M., Aguilar L., Straathof K. C., Gahn B., Huls M. H., Rousseau A., Sixbey J., Gresik M. V., Carrum G. other authors 2004; Cytotoxic T lymphocyte therapy for Epstein-Barr virus+ Hodgkin's disease. J Exp Med 200:1623–1633 [CrossRef]
     [Google Scholar]
  8. Callan M. F., Tan L., Annels N., Ogg G. S., Wilson J. D., O'Callaghan C. A., Steven N., McMichael A. J., Rickinson A. B. 1998; Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr virus in vivo. J Exp Med 187:1395–1402 [CrossRef]
     [Google Scholar]
  9. Coulie P. G., Karanikas V., Colau D., Lurquin C., Landry C., Marchand M., Dorval T., Brichard V., Boon T. 2001; A monoclonal cytolytic T-lymphocyte response observed in a melanoma patient vaccinated with a tumor-specific antigenic peptide encoded by gene MAGE-3. Proc Natl Acad Sci U S A 98:10290–10295 [CrossRef]
     [Google Scholar]
  10. Dauer M., Obermaier B., Herten J., Haerle C., Pohl K., Rothenfusser S., Schnurr M., Endres S., Eigler A. 2003; Mature dendritic cells derived from human monocytes within 48 hours: a novel strategy for dendritic cell differentiation from blood precursors. J Immunol 170:4069–4076 [CrossRef]
     [Google Scholar]
  11. Gottschalk S., Rooney C. M., Heslop H. E. 2005; Post-transplant lymphoproliferative disorders. Annu Rev Med 56:29–44 [CrossRef]
     [Google Scholar]
  12. Grunebach F., Muller M. R., Nencioni A., Brossart P. 2003; Delivery of tumor-derived RNA for the induction of cytotoxic T-lymphocytes. Gene Ther 10:367–374 [CrossRef]
     [Google Scholar]
  13. Heiser A., Dahm P., Yancey D. R., Maurice M. A., Boczkowski D., Nair S. K., Gilboa E., Vieweg J. 2000; Human dendritic cells transfected with RNA encoding prostate-specific antigen stimulate prostate-specific CTL responses in vitro. J Immunol 164:5508–5514 [CrossRef]
     [Google Scholar]
  14. Heiser A., Coleman D., Dannull J., Yancey D., Maurice M. A., Lallas C. D., Dahm P., Niedzwiecki D., Gilboa E., Vieweg J. 2002; Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors. J Clin Invest 109:409–417 [CrossRef]
     [Google Scholar]
  15. Hong W., Fu Y., Chen S., Wang F., Ren X., Xu A. 2005; Distributions of HLA class I alleles and haplotypes in Northern Han Chinese. Tissue Antigens 66:297–304 [CrossRef]
     [Google Scholar]
  16. Khanna R., Burrows S. R., Kurilla M. G., Jacob C. A., Misko I. S., Sculley T. B., Kieff E., Moss D. J. 1992; Localization of Epstein-Barr virus cytotoxic T cell epitopes using recombinant vaccinia: implications for vaccine development. J Exp Med 176:169–176 [CrossRef]
     [Google Scholar]
  17. Khanna R., Burrows S. R., Steigerwald-Mullen P. M., Thomson S. A., Kurilla M. G., Moss D. J. 1995; Isolation of cytotoxic T lymphocytes from healthy seropositive individuals specific for peptide epitopes from Epstein-Barr virus nuclear antigen 1: implications for viral persistence and tumor surveillance. Virology 214:633–637 [CrossRef]
     [Google Scholar]
  18. Khanna R., Burrows S. R., Steigerwald-Mullen P. M., Moss D. J., Kurilla M. G., Cooper L. 1997; Targeting Epstein-Barr virus nuclear antigen 1 (EBNA1) through the class II pathway restores immune recognition by EBNA1-specific cytotoxic T lymphocytes: evidence for HLA-DM-independent processing. Int Immunol 9:1537–1543 [CrossRef]
     [Google Scholar]
  19. Kieff E., Rickinson A. B. 2001; Epstein-Barr virus and its replication. In Fields Virology , 4th edn. pp  2511–2573 Edited by Knipe D. M., Howley P. M. Philadelphia, PA: Lippincott Williams & Wilkins;
     [Google Scholar]
  20. Kondo E., Topp M. S., Kiem H. P., Obata Y., Morishima Y., Kuzushima K., Tanimoto M., Harada M., Takahashi T., Akatsuka Y. 2002; Efficient generation of antigen-specific cytotoxic T cells using retrovirally transduced CD40-activated B cells. J Immunol 169:2164–2171 [CrossRef]
     [Google Scholar]
  21. Kruger S., Schroers R., Rooney C. M., Gahn B., Chen S. Y. 2003; Identification of a naturally processed HLA-DR-restricted T-helper epitope in Epstein-Barr virus nuclear antigen type 1. J Immunother 26:212–221 [CrossRef]
     [Google Scholar]
  22. Kuzushima K., Hoshino Y., Fujii K., Yokoyama N., Fujita M., Kiyono T., Kimura H., Morishima T., Morishima Y., Tsurumi T. 1999; Rapid determination of Epstein-Barr virus-specific CD8(+) T-cell frequencies by flow cytometry. Blood 94:3094–3100
     [Google Scholar]
  23. Kuzushima K., Hayashi N., Kimura H., Tsurumi T. 2001; Efficient identification of HLA-A*2402-restricted cytomegalovirus-specific CD8(+) T-cell epitopes by a computer algorithm and an enzyme-linked immunospot assay. Blood 98:1872–1881 [CrossRef]
     [Google Scholar]
  24. Kuzushima K., Hayashi N., Kudoh A., Akatsuka Y., Tsujimura K., Morishima Y., Tsurumi T. 2003; Tetramer-assisted identification and characterization of epitopes recognized by HLA A*2402-restricted Epstein-Barr virus-specific CD8+ T cells. Blood 101:1460–1468 [CrossRef]
     [Google Scholar]
  25. Lee S. P., Brooks J. M., Al-Jarrah H., Thomas W. A., Haigh T. A., Taylor G. S., Humme S., Schepers A., Hammerschmidt W. other authors 2004; CD8 T cell recognition of endogenously expressed Epstein-Barr virus nuclear antigen 1. J Exp Med 199:1409–1420 [CrossRef]
     [Google Scholar]
  26. Leen A., Meij P., Redchenko I., Middeldorp J., Bloemena E., Rickinson A., Blake N. 2001; Differential immunogenicity of Epstein-Barr virus latent-cycle proteins for human CD4(+) T-helper 1 responses. J Virol 75:8649–8659 [CrossRef]
     [Google Scholar]
  27. Levitskaya J., Coram M., Levitsky V., Imreh S., Steigerwald-Mullen P. M., Klein G., Kurilla M. G., Masucci M. G. 1995; Inhibition of antigen processing by the internal repeat region of the Epstein-Barr virus nuclear antigen-1. Nature 375:685–688 [CrossRef]
     [Google Scholar]
  28. Levitskaya J., Sharipo A., Leonchiks A., Ciechanover A., Masucci M. G. 1997; Inhibition of ubiquitin/proteasome-dependent protein degradation by the Gly-Ala repeat domain of the Epstein-Barr virus nuclear antigen 1. Proc Natl Acad Sci U S A 94:12616–12621 [CrossRef]
     [Google Scholar]
  29. Muller M. R., Tsakou G., Grunebach F., Schmidt S. M., Brossart P. 2004; Induction of chronic lymphocytic leukemia (CLL)-specific CD4- and CD8-mediated T-cell responses using RNA-transfected dendritic cells. Blood 103:1763–1769 [CrossRef]
     [Google Scholar]
  30. Munz C., Bickham K. L., Subklewe M., Tsang M. L., Chahroudi A., Kurilla M. G., Zhang D., O'Donnell M., Steinman R. M. 2000; Human CD4(+) T lymphocytes consistently respond to the latent Epstein-Barr virus nuclear antigen EBNA1. J Exp Med 191:1649–1660 [CrossRef]
     [Google Scholar]
  31. Murray R. J., Kurilla M. G., Brooks J. M., Thomas W. A., Rowe M., Kieff E., Rickinson A. B. 1992; Identification of target antigens for the human cytotoxic T cell response to Epstein-Barr virus (EBV): implications for the immune control of EBV-positive malignancies. J Exp Med 176:157–168 [CrossRef]
     [Google Scholar]
  32. Nair S. K., Boczkowski D., Morse M., Cumming R. I., Lyerly H. K., Gilboa E. 1998; Induction of primary carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocytes in vitro using human dendritic cells transfected with RNA. Nat Biotechnol 16:364–369 [CrossRef]
     [Google Scholar]
  33. Nair S. K., Heiser A., Boczkowski D., Majumdar A., Naoe M., Lebkowski J. S., Vieweg J., Gilboa E. 2000; Induction of cytotoxic T cell responses and tumor immunity against unrelated tumors using telomerase reverse transcriptase RNA transfected dendritic cells. Nat Med 6:1011–1017 [CrossRef]
     [Google Scholar]
  34. Paludan C., Bickham K., Nikiforow S., Tsang M. L., Goodman K., Hanekom W. A., Fonteneau J. F., Stevanovic S., Munz C. 2002; Epstein-Barr nuclear antigen 1-specific CD4(+) Th1 cells kill Burkitt's lymphoma cells. J Immunol 169:1593–1603 [CrossRef]
     [Google Scholar]
  35. Rammensee H., Bachmann J., Emmerich N. P., Bachor O. A., Stevanovic S. 1999; syfpeithi: database for MHC ligands and peptide motifs. Immunogenetics 50:213–219 [CrossRef]
     [Google Scholar]
  36. Rickinson A. B., Moss D. J. 1997; Human cytotoxic T lymphocyte responses to Epstein-Barr virus infection. Annu Rev Immunol 15:405–431 [CrossRef]
     [Google Scholar]
  37. Rickinson A. B., Kieff E. 2001; Epstein-Barr Virus. In Fields Virology , 4th edn. pp  2575–2627 Edited by Knipe D. M., Howley P. M. Philadelphia, PA: Lippincott Williams & Wilkins;
     [Google Scholar]
  38. Romani N., Gruner S., Brang D., Kampgen E., Lenz A., Trockenbacher B., Konwalinka G., Fritsch P. O., Steinman R. M., Schuler G. 1994; Proliferating dendritic cell progenitors in human blood. J Exp Med 180:83–93 [CrossRef]
     [Google Scholar]
  39. Sallusto F., Lanzavecchia A. 1994; Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med 179:1109–1118 [CrossRef]
     [Google Scholar]
  40. Schultze J. L., Michalak S., Seamon M. J., Dranoff G., Jung K., Daley J., Delgado J. C., Gribben J. G., Nadler L. M. 1997; CD40-activated human B cells: an alternative source of highly efficient antigen presenting cells to generate autologous antigen-specific T cells for adoptive immunotherapy. J Clin Invest 100:2757–2765 [CrossRef]
     [Google Scholar]
  41. Steven N. M., Leese A. M., Annels N. E., Lee S. P., Rickinson A. B. 1996; Epitope focusing in the primary cytotoxic T cell response to Epstein-Barr virus and its relationship to T cell memory. J Exp Med 184:1801–1813 [CrossRef]
     [Google Scholar]
  42. Straathof K. C., Bollard C. M., Popat U., Huls M. H., Lopez T., Morriss M. C., Gresik M. V., Gee A. P., Russell H. V. other authors 2005; Treatment of nasopharyngeal carcinoma with Epstein-Barr virus-specific T lymphocytes. Blood 105:1898–1904 [CrossRef]
     [Google Scholar]
  43. Su Z., Dannull J., Heiser A., Yancey D., Pruitt S., Madden J., Coleman D., Niedzwiecki D., Gilboa E., Vieweg J. 2003; Immunological and clinical responses in metastatic renal cancer patients vaccinated with tumor RNA-transfected dendritic cells. Cancer Res 63:2127–2133
     [Google Scholar]
  44. Tellam J., Connolly G., Green K. J., Miles J. J., Moss D. J., Burrows S. R., Khanna R. 2004; Endogenous presentation of CD8+ T cell epitopes from Epstein-Barr virus-encoded nuclear antigen 1. J Exp Med 199:1421–1431 [CrossRef]
     [Google Scholar]
  45. Van Tendeloo V. F., Ponsaerts P., Lardon F., Nijs G., Lenjou M., Van Broeckhoven C., Van Bockstaele D. R., Berneman Z. N. 2001; Highly efficient gene delivery by mRNA electroporation in human hematopoietic cells: superiority to lipofection and passive pulsing of mRNA and to electroporation of plasmid cDNA for tumor antigen loading of dendritic cells. Blood 98:49–56 [CrossRef]
     [Google Scholar]
  46. Voo K. S., Fu T., Heslop H. E., Brenner M. K., Rooney C. M., Wang R. F. 2002; Identification of HLA-DP3-restricted peptides from EBNA1 recognized by CD4(+) T cells. Cancer Res 62:7195–7199
     [Google Scholar]
  47. Voo K. S., Fu T., Wang H. Y., Tellam J., Heslop H. E., Brenner M. K., Rooney C. M., Wang R. F. 2004; Evidence for the presentation of major histocompatibility complex class I-restricted Epstein-Barr virus nuclear antigen 1 peptides to CD8+ T lymphocytes. J Exp Med 199:459–470 [CrossRef]
     [Google Scholar]
  48. Yin Y., Manoury B., Fahraeus R. 2003; Self-inhibition of synthesis and antigen presentation by Epstein-Barr virus-encoded EBNA1. Science 301:1371–1374 [CrossRef]
     [Google Scholar]
  49. Zeis M., Siegel S., Wagner A., Schmitz M., Marget M., Kuhl-Burmeister R., Adamzik I., Kabelitz D., Dreger P. other authors 2003; Generation of cytotoxic responses in mice and human individuals against hematological malignancies using survivin-RNA-transfected dendritic cells. J Immunol 170:5391–5397 [CrossRef]
     [Google Scholar]
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Full-length EBNA1 mRNA-transduced dendritic cells stimulate cytotoxic T lymphocytes recognizing a novel HLA-Cw*0303- and -Cw*0304-restricted epitope on EBNA1-expressing cells
J. Gen. Virol. 88, 770 (2007); https://doi.org/10.1099/vir.0.82519-0
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