Research of Epstein-Barr virus-specific T cell immunity targeting the virus-positive cancer

• Project/Area Number: 17590428
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Virology
• Research Institution: Aichi Cancer Center Research Institute
• Principal Investigator: KUZUSHIMA Kiyotaka Aichi Cancer Center, Division of Immunology, Chief, 腫瘍免疫学部, 部長 (30311442)
• Co-Investigator(Kenkyū-buntansha): 伊藤 嘉規 愛知県がんセンター(研究所), 腫瘍免疫学部, 主任研究員 (20373491)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000); Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: Epstein-Barr virus / CD4^+ T cells / EBNA1 / HLA / lymphoma / 細胞傷害性Tリンパ / ヘルパーT細胞 / EBNA / 細胞傷害性Tリンパ球 / 胃癌 / 上咽頭癌 / ホジキンリンパ腫

Research Abstract

Epstein-Barr virus (EBV) nuclear antigen (EBNA) 1 is expressed in every EBV-infected cell, regardless of the state of EBV infection. Although EBNA1 is thought to be a promising antigen (Ag) for immunotherapy of all EBV-associated malignancies, it is less clear whether EBNA1-specific CD4^+ T cells can act as direct effectors. Here, we investigated the ability of CD4^+ T cell clones induced with overlapping peptides covering the C-terminal region of EBNA1, and identified minimal epitopes and their restricted MHC class II molecules. Of these, a novel epitope was found to be is presented by DRB1^*0401, 0403, and 0406. Five CD4^+ T cell clones recognized endogenously processed and presented antigens on EBV-transformed lymphoblastoid cell lines and one example proved capable of killing EBV-carrying NK and T cell lines derived from patients with chronic active EBV infection. Identification of minimal epitopes facilitates design of peptide-based vaccines and our data suggest that EBNA1-specific CD4^+ T cells may play roles as direct effectors for immunotherapy targeting EBV-carrying NK and T cell malignancies.

Research Products

• [Journal Article] Full-length EBNA1-mRNA-transduced dendritic cells stimulate CTLs recognizing a novel HLA-Cw*0303 and Cw*0304-restricted epitope on EBNA1-expressing cells. (2007)
  • Author(s): Ito Y.
  • Journal Title: J Gen Virol. 88(Pt 3) Pages: 770-780
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of an HLA-A24-restricted cytotoxic T lymphocyte epitope from human papillomavirus type-16 E6 : the combined effects of bortezomib and interferon-γ on the presentation of a cryptic epitope. (2007)
  • Author(s): Morishima S.
  • Journal Title: Int J Cancer. 120(3) Pages: 594-604
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Full-length EBNA1-mRNA-transduced dendritic cells stimulate CTLs recognizing a novel HLA-Cw^*0303 and Cw^*0304-restricted epitope on EBNA1-expressing cells. (2007)
  • Author(s): Ito Y, Demachi-Okamura, A, Ohta R, Akatsuka Y, Nishida K, Tsujimura K, Morishima Y, Takahashi T, Kuzushima K.
  • Journal Title: J Gen.Virol. 88(Pt 3) Pages: 770-80
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of an HLA-A24-restricted cytotoxic T lymphocyte epitope from human papillomavirus type-16 E6 : The combined effects of bortezomib and interferon-gamma on the presentation of a cryptic epitope. (2007)
  • Author(s): Morishima S, Akatsuka Y, Nawa A, Kondo E, Kiyono T, Torikai H, Nakanishi T, Ito Y, Tsujimura K, Iwata K, Ito K, Kodera Y, Morishima Y, Kuzushima K, Takahashi T
  • Journal Title: Int J Cancer. 120 Pages: 594-604
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Full-length EBNA1-mRNA-transduced dendritic cells stimulate CTLs recognizing a novel HLA-Cw*0303 and Cw*0304-restricted epitope on EBNA1-expressing cells. (2007)
  • Author(s): Ito Y
  • Journal Title: J Gen Virol. 88(Pt 3) Pages: 770-80
• [Journal Article] Epstein-Barr virus (EBV) latent membrane protein l-specific cytotoxic Tlymphocytes targeting natural killer cell malignancies carrying EBV. (2006)
  • Author(s): Demachi-Okamura A.
  • Journal Title: Eur J Immunol. 36(3) Pages: 593-602
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Three Immunoproteasome-Associated Subunits Cooperatively Generate a CTL Epitope of the EBV LMP2A by Overcoming Specific Structures Resistant to Epitope Liberation. (2006)
  • Author(s): Ito Y.
  • Journal Title: J Virol. 80(2) Pages: 883-890
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Bone marrow may be a reservoir of long-lived memory T cells specific for minor histocompatibility antigen. (2006)
  • Author(s): Akatsuka Y.
  • Journal Title: Br J Haematol. 135(3) Pages: 413-414
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The human cathepsin H gene encodes two novel minor histocompatibility antigen epitopes restricted by HLA-A*3101 and -A*3303. (2006)
  • Author(s): Torikai H.
  • Journal Title: Br J Haematol. 134(4) Pages: 406-416
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Epstein-Barr virus (EBV) latent membrane protein 1-specific cytotoxic T lymphocytes targeting natural killer cell malignancies carrying EBV. (2006)
  • Author(s): Demachi-Okamura, A., Ito, Y., Akatsuka, Y., Tsujimura, K., Morishima, Y., Takahashi, T., Kuzushima, K.
  • Journal Title: Eur.J.Immunol 36(3) Pages: 593-602
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Three Immunoproteasome-Associated Subunits Cooperatively Generate a CTL Epitope of the EBV LMP2A by Overcoming Specific Structures Resistant to Epitope Liberation. (2006)
  • Author(s): Ito, Y., Kondo, E., Demachi-Okamura, A., Akatsuka, Y., Tsujimura, K., Tanimoto, M., Morishima, Y., Takahashi, T., Kuzushima, K.
  • Journal Title: J Virol 80(2) Pages: 883-890
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Bone marrow may be a reservoir of long-lived memory T cells specific for minor histocompatibility antigen. (2006)
  • Author(s): Akatsuka Y, Torikai H, Inamoto Y, Tsujimura K, Morishima Y, Kodera Y, Kuzushima K, Takahashi T
  • Journal Title: Br J Haematol 135(3) Pages: 413-414
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The human cathepsin H gene encodes two novel minor histocompatibility antigen epitopes restricted by HLA-A^*3101 and-A^*3303. (2006)
  • Author(s): Torikai H, Akatsuka Y, Miyazaki M, Tsujimura A, Yatabe Y, Kawase T, Nakao Y, Tsujimura K, Motoyoshi K, Morishima Y, Kodera Y, Kuzushima K, Takahashi T
  • Journal Title: Br J Haematol 134(4) Pages: 406-416
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Epstein-Barr virus (EBV) latent membrane protein 1-specific 1-specific cytotoxic T lymphocytes targeting natural killer cell malignancies carrying EBV. (2006)
  • Author(s): Demachi-Okamura A.
  • Journal Title: Eur J Immunol. 36(3) Pages: 593-602
• [Journal Article] Therr Immunoproteasome-Associated Subunits Cooperatively Generate a CTL Epitope of the EBV LMP2A by Overcoming Specific Structures Resistant to Epitope Liberation. (2006)
  • Author(s): Ito Y.
  • Journal Title: J Virol. 80(2) Pages: 883-90
• [Journal Article] Epstein-Barr virus (EBV) latent membrane protein-1-specific cytotoxic T lymphocytes targeting EBV-carrying natural killer cell malignancies. (2006)
  • Author(s): Demachi-Okamura A.
  • Journal Title: Eur J Immunol. (2006 Feb 14;[Epub ahead of print])
• [Journal Article] Three immunoproteasome-associate subunits cooperatively generate a cytotoxic T-lymphocyte epitope of Epstein-Barr virus LMP2A by overcoming specific structures resistant to epitope liberation. (2006)
  • Author(s): Ito Y.
  • Journal Title: J Virol. 80(2) Pages: 883-890
• [Journal Article] Differences between T Cell-Type and Natural Killer Cell-Type Chronic Active Epstein-Barr Virus Infection. (2005)
  • Author(s): Kimura H, Hoshino Y, Hara S, Sugaya N, Kawada J, Shibata Y, Kojima S, Nagasaka T, Kuzushima K, Morishima T
  • Journal Title: J.Infect.Dis. 191(4) Pages: 531-539
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Retroviral vector backbone immunogenicity : identification of cytotoxic T-cell epitopes in retroviral vector-packaging sequences. (2005)
  • Author(s): Kondo E, Akatsuka Y, Nawa A, Kuzushima K, Tsujimura K, Tanimoto M, Kodera Y, Morishima Y, Kuzuya K, Takahashi T
  • Journal Title: Gene Ther. 12(3) Pages: 252-258
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Generation of tumor-specific, HLA class I-restricted human Th1 and Tc1 cells by cell engineering with tumor peptide-specific T-cell receptor genes. (2005)
  • Author(s): Tsuji, T., Yasukawa, M., Matsuzaki, J., Ohkuri, T., Chamoto, K., Wakita, D., Azuma, T., Niiya, H., Miyoshi, H., Kuzushima.K., Oka, Y., Sugiyama, H., Ikeda, H., Nishimura, T.
  • Journal Title: Blood. 106(2) Pages: 470-476
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Differences between T cell-type and natural killer cell-type chronic active Epstein-Barr virus infection. (2005)
  • Author(s): Kimura H.
  • Journal Title: J Infect Dis. 191(4) Pages: 531-539