Identification of HLA DR7-restricted epitopes from human telomerase reverse transcriptase recognized by CD4+ T-helper cells.
CD4+ T cells play critical roles in initiating, regulating, and maintaining antitumor immune responses. One way to improve current tumor vaccines that mainly induce CTLs would be to activate antigen-specific CD4+ T cells that recognize MHC class II restricted tumor associated antigens. Human telomerase reverse transcriptase (hTRT) is preferentially expressed by various tumors and, therefore, could be a universal tumor antigen. In this study, we used a combined approach of using the prediction software TEPITOPE to select class II epitope candidates and in vitro T-cell biological analysis to identify class II-restricted epitope(s) in hTRT. We first identified several HLA-DR7-restricted class-II epitope candidates in hTRT by examining human T-cell responses to synthetic peptides. We then characterized these HLA-DR7-restricted hTRT epitope candidates by establishing and analyzing peptide-specific T-cell clones. It was demonstrated that CD4+ T cells specific for the HLA-DR7-restricted hTRT(672) epitope (RPGLLGASVLGLDDI) can respond to naturally processed hTRT proteins. Furthermore, the hTRT(672)-specific T cells recognized hTRT antigen from various tumors, including prostate cancer, breast cancer, melanoma, and leukemia. Thus, the identification of the naturally processed HLA-DR7-restricted hTRT epitope, together with the previous finding of class I-restricted hTRT epitopes, provide a basis for the combined application of class I- and II-restricted hTRT epitopes to induce potent, long-term CD4+ and CD8+ T-cell responses against a broad spectrum of tumors.
Schroers
Roland
R
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas 77030, USA.
Huang
Xue F
XF
Hammer
Juergen
J
Zhang
Jingwu
J
Chen
Si-Yi
SY
D000595:Amino Acid Sequence; D000915:Antibody Affinity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004268:DNA-Binding Proteins; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D015809:HLA-DR7 Antigen / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D019098:Telomerase / Q000276:immunology*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D015809:HLA-DR7 Antigen; D010446:Peptide Fragments; D019098:Telomerase