1. Identification of multiple HLA-DR-restricted epitopes of the tumor-associated antigen CAMEL by CD4+ Th1/Th2 lymphocytes.
- Author
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Slager EH, van der Minne CE, Krüse M, Krueger DD, Griffioen M, and Osanto S
- Subjects
- Amino Acid Sequence, Antigen Presentation, Antigens, Neoplasm immunology, Antigens, Neoplasm metabolism, Antigens, Surface, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Cell Line, Transformed, Cell Line, Tumor, Clone Cells, Epitopes, T-Lymphocyte immunology, Epitopes, T-Lymphocyte metabolism, HLA-DR Antigens immunology, HLA-DR Antigens metabolism, Humans, Lymphocyte Activation immunology, Melanoma immunology, Melanoma metabolism, Membrane Proteins immunology, Membrane Proteins metabolism, Molecular Sequence Data, Peptide Fragments analysis, Peptide Fragments immunology, Protein Binding immunology, Recombinant Proteins immunology, Recombinant Proteins metabolism, Antigens, Neoplasm analysis, Epitopes, T-Lymphocyte analysis, HLA-DR Antigens analysis, Membrane Proteins analysis, Th1 Cells immunology, Th1 Cells metabolism, Th2 Cells immunology, Th2 Cells metabolism
- Abstract
CD4(+) Th cells play an important role in the induction and maintenance of adequate CD8(+) T cell-mediated antitumor responses. Therefore, identification of MHC class II-restricted tumor antigenic epitopes is of major importance for the development of effective immunotherapies with synthetic peptides. CAMEL and NY-ESO-ORF2 are tumor Ags translated in an alternative open reading frame from the highly homologous LAGE-1 and NY-ESO-1 genes, respectively. In this study, we investigated whether CD4(+) T cell responses could be induced in vitro by autologous, mature dendritic cells pulsed with recombinant CAMEL protein. The data show efficient induction of CAMEL-specific CD4(+) T cells with mixed Th1/Th2 phenotype in two healthy donors. Isolation of CD4(+) T cell clones from the T cell cultures of both donors led to the identification of four naturally processed HLA-DR-binding CAMEL epitopes: CAMEL(1-20), CAMEL(14-33), CAMEL(46-65), and CAMEL(81-102). Two peptides (CAMEL(1-20) and CAMEL(14-33)) also contain previously identified HLA class I-binding CD8(+) T cell epitopes shared by CAMEL and NY-ESO-ORF2 and are therefore interesting tools to explore for immunotherapy. Furthermore, two CD4(+) T cell clones that recognized the CAMEL(14-33) peptide with similar affinities were shown to differ in recognition of tumor cells. These CD4(+) T cell clones recognized the same minimal epitope and expressed similar levels of adhesion, costimulatory, and inhibitory molecules. TCR analysis demonstrated that these clones expressed identical TCR beta-chains, but different complementarity-determining region 3 loops of the TCR alpha-chains. Introduction of the TCRs into proper recipient cells should reveal whether the different complementarity-determining region 3 alpha loops are important for tumor cell recognition.
- Published
- 2004
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