Identification of new NY-ESO-1 epitopes recognized by CD4+ T cells and presented by HLA-DQ B1 03011.
NY-ESO-1 is one of the most immunogenic cancer antigens eliciting strong humoral and cellular immune responses in patients with NY-ESO-1-expressing malignancies. Since CD4+ T cells play a critical role in generating and maintaining antigen-specific cellular and humoral immune responses, we searched for new NY-ESO-1 epitopes presented by MHC class II molecules. CD4+ T cells of patients with NY-ESO-1-expressing cancer were presensitized with 18-mer overlapping synthetic peptides spanning the entire sequence of NY-ESO-1. Two partly overlapping NY-ESO-1 epitopes p49-66 and p55-72 were identified as targets for NY-ESO-1-specific CD4+ T cells. Peptide-specific CD4+ T-cell clones were generated by repetitive stimulation with NY-ESO-1 p49-66 and p55-72. Further experiments confirmed distinct specificities for the CD4+ T-cell clones indicating that at least 2 different CD4+ T-cell epitopes are located in the region p49-72 of the NY-ESO-1 sequence. Using a set of partially histocompatible EBV-B cell lines and MHC class II-specific antibodies, we found that both CD4+ T-cell epitopes were presented in the context of HLA-DQ B1 03011(DQ7). Natural processing and presentation of these epitopes was demonstrated by recognition of an HLA-DQ B1 03011- and NY-ESO-1-expressing lymphoma cell line and by recognition of dendritic cells (DC) exogenously loaded with NY-ESO-1 protein or infected with recombinant NY-ESO-1 adenoviral constructs. The specific production of IFN-gamma and TNF-alpha suggests that the NY-ESO-1-specific CD4+ T-cell clones belong to the Th1 subtype. The characterization of the new HLA-DQ B1 03011-restricted NY-ESO-1 peptides broadens the repertoire of epitopes that can be used to monitor NY-ESO-1-specific spontaneous and vaccine-induced T-cell responses in cancer patients.
Karbach
Julia
J
II. Medizinische Klinik, Hämatologie-Onkologie, Krankenhaus Nordwest, Frankfurt, Germany.
Pauligk
Claudia
C
Bender
Armin
A
Gnjatic
Sacha
S
Franzmann
Kerstin
K
Wahle
Claudia
C
Jäger
Dirk
D
Knuth
Alexander
A
Old
Lloyd J
LJ
Jäger
Elke
E
D000256:Adenoviridae / Q000235:genetics; D000595:Amino Acid Sequence; D000938:Antigen-Presenting Cells / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002461:Cell Line, Transformed / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells; D016889:Endometrial Neoplasms / Q000276:immunology / Q000556:secondary; D000939:Epitopes / Q000276:immunology*; D005260:Female; D006683:HLA-DQ Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D004854:Herpesvirus 4, Human; D006801:Humans; D008223:Lymphoma / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000556:secondary; D008565:Membrane Proteins / Q000276:immunology*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology; D013584:Sarcoma, Synovial / Q000276:immunology / Q000556:secondary; D013737:Testis
D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D000939:Epitopes; D006683:HLA-DQ Antigens; D008565:Membrane Proteins; D010446:Peptide Fragments; D011994:Recombinant Proteins