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-1Tax 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-1Tax 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][192][193][194][195][196][197][198][199][200][201][202][203][204][205] was restricted by the HLA-DR1 and DR9 alleles, responses to Tax [305][306][307][308][309][310][311][312][313][314][315][316][317][318][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-1Tax + 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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