Identification of a naturally processed HLA-DR-restricted T-helper epitope in Epstein-Barr virus nuclear antigen type 1.
Epstein-Barr virus nuclear antigen type 1 (EBNA1), the only viral protein that is unequivocally expressed in all Epstein-Barr virus (EBV)-associated malignant diseases, is essential for viral DNA replication and maintenance of the viral episome in infected cells. A glycine-alanine repeat domain inhibits antigen processing through the ubiquitin-proteasome pathway for presentation on human leukocyte antigen (HLA) class I molecules. EBNA1 is not protected from the HLA class II processing pathway, and CD4+ HLA class II-restricted T cells recognize the antigen. CD4+ T-helper (Th) cells play critical roles in initiating, regulating, and maintaining immune responses against viral infections and tumors, so that inclusion of EBNA1 as a target antigen may improve immunotherapy for EBV-associated cancers. In this study, the authors used the TEPITOPE software program to predict promiscuous class II epitope candidates. After several HLA-DR-restricted peptides were identified by in vitro analysis of the T-cell response to synthetic peptides, a T-cell clone was established that was specific for one of the peptides. Functional studies were performed with this clone. The CD4+ T helper cells specific for the HLA-DR15-restricted peptide EBNA1(482) (AEGLRALLARSHVER) recognized naturally processed EBNA1 protein. This epitope was presented by several HLA-DR alleles, including DR4, DR7, and DR11. The inclusion of the promiscuous, naturally processed EBNA1(482) epitope in vaccine constructs could enhance immune responses against EBV-positive cancers.
Krüger
Stefan
S
Center for Cell and Gene Therapy, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Schroers
Roland
R
Rooney
Cliona M
CM
Gahn
Benedikt
B
Chen
Si-Yi
SY
D000483:Alleles; D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D018984:Epitopes, T-Lymphocyte; D019309:Epstein-Barr Virus Nuclear Antigens / Q000276:immunology*; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data
D018984:Epitopes, T-Lymphocyte; D019309:Epstein-Barr Virus Nuclear Antigens; D006684:HLA-DR Antigens; C417029:EBV-encoded nuclear antigen 1