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In vitro Peptide Immunization of Target Tax Protein Human T-Cell Leukemia Virus Type 1–Specific CD4⁺ Helper T Lymphocytes

Authors' Affiliations: Departments of ¹ Pathology and ² Internal Medicine, Asahikawa Medical College, Asahikawa, Japan; ³ Department of Immunology, University of Ryukyus, Okinawa, Japan; and ⁴ H. Lee Moffitt Cancer Center, University of South Florida, Tampa, Florida

Requests for reprints: Hiroya Kobayashi, Department of Pathology, Asahikawa Medical College, Midorigaoka-Higashi 2-1-1, Asahikawa 078-8510, Japan. Phone: 81-166-68-2381; Fax: 81-166-68-2389; E-mail: hiroya{at}asahikawa-med.ac.jp.

Purpose: Adult T-cell leukemia/lymphoma induced by human T-cell leukemia virus type 1 (HTLV-1) is usually a fatal lymphoproliferative malignant disease. HTLV-1 Tax protein plays a critical role in HTLV-1-associated leukemogenesis and is an attractive target for vaccine development. Although HTLV-1 Tax is the most dominant antigen for HTLV-1-specific CD8⁺ CTLs in HTLV-1-infected individuals, few epitopes recognized by CD4⁺ helper T lymphocytes in HTLV-1 Tax protein have been described. The aim of the present study was to study T-helper-cell responses to HTLV-1 Tax and to identify naturally processed MHC class II–restricted epitopes that could be used for vaccine development.

Experimental Design: An MHC class II binding peptide algorithm was used to predict potential T-helper cell epitope peptides from HTLV-1 Tax. We assessed the ability of the corresponding peptides to elicit helper T-cell responses by in vitro vaccination of purified CD4⁺ T lymphocytes.

Results: Peptides Tax_191-205 and Tax_305-319 were effective in inducing T-helper-cell responses. Although Tax_191-205 was restricted by the HLA-DR1 and DR9 alleles, responses to Tax_305-319 were restricted by either DR15 or DQ9. Both these epitopes were found to be naturally processed by HTLV-1⁺ T-cell lymphoma cells and by autologous antigen-presenting cells that were pulsed with HTLV-1 Tax⁺ tumor lysates. Notably, the two newly identified helper T-cell epitopes are found to lie proximal to known CTL epitopes, which will facilitate the development of prophylactic peptide–based vaccine capable of inducing simultaneous CTL and T-helper responses.

Conclusion: Our data suggest that HTLV-1 Tax protein could serve as tumor-associated antigen for CD4⁺ helper T cells and that the present epitopes might be used for T-cell-based immunotherapy against tumors expressing HTLV-1.

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