The B subunit of Escherichia coli heat-labile enterotoxin enhances CD8+ cytotoxic-T-lymphocyte killing of Epstein-Barr virus-infected cell lines.
Epstein-Barr virus (EBV) is associated with a number of important human cancers, including nasopharyngeal carcinoma, gastric carcinoma, and Hodgkin's lymphoma. These tumors express a viral nuclear antigen, EBV nuclear antigen 1 (EBNA1), which cannot be presented to T cells in a major histocompatibility complex class I context, and the viral latent membrane proteins (LMPs). Although the LMPs are expressed in these tumors, no effective immune response is made. We report here that exposure to the cholera-like enterotoxin B subunit (EtxB) in EBV-infected lymphoblastoid cell lines (LCLs) enhances their susceptibility to killing by LMP-specific CD8(+) cytotoxic T lymphocytes (CTLs) in a HLA class I-restricted manner. CTL killing of LCLs is dramatically increased through both transporter-associated protein-dependent and -independent epitopes after EtxB treatment. The use of mutant B subunits revealed that the enhanced susceptibility of LCLs to CTL killing is dependent on the B subunit's interaction with GM(1) but not its signaling properties. These important findings could underpin the development of novel approaches to treating EBV-associated malignancies and may offer a general approach to increasing the presentation of other tumor and viral antigens.
Ong
Kong-Wee
KW
Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, United Kingdom.
Wilson
A Douglas
AD
Hirst
Timothy R
TR
Morgan
Andrew J
AJ
D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000187:drug effects; D001427:Bacterial Toxins / Q000276:immunology / Q000494:pharmacology*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000276:immunology / Q000821:virology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D004768:Enterotoxins / Q000276:immunology / Q000494:pharmacology*; D000939:Epitopes / Q000235:genetics; D020031:Epstein-Barr Virus Infections / Q000276:immunology / Q000628:therapy; D029968:Escherichia coli Proteins; D005677:G(M1) Ganglioside / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism
D001427:Bacterial Toxins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D004768:Enterotoxins; D000939:Epitopes; D029968:Escherichia coli Proteins; D015395:Histocompatibility Antigens Class I; D009097:Multienzyme Complexes; D014763:Viral Matrix Proteins; D005677:G(M1) Ganglioside; C027538:heat-labile enterotoxin, E coli; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex