Endoplasmic reticulum signal sequence facilitated transport of peptide epitopes restores immunogenicity of an antigen processing defective tumour cell line.
The identification of MHC-restricted and tumour-specific cytotoxic T lymphocytes (CTLs) provides strong evidence in support of T cell-mediated immune surveillance against human tumour cells. These CTLs recognize short peptides derived from tumour-associated antigens in conjunction with class I molecules expressed on tumour cells. In contrast to these observations there are now numerous examples to suggest that a number of tumours escape this CTL-mediated control either by down-regulating accessory molecules or by blocking the intracellular processing of tumour-specific antigens. Recently a number of tumour cell lines have been identified which display a transcriptional deficiency of transporters associated with antigen processing (also referred to as TAP). The Epstein-Barr virus (EBV)-associated tumour, Burkitt's lymphoma (BL), is a classic example in this category. In the present study we have restored class I-restricted antigen processing in a BL cell line by transfecting a minigene expression vector encoding a CTL epitope derived from EBV linked to an endoplasmic reticulum translocation signal sequence. These minigene transfected BL cells were not only susceptible to lysis by virus-specific CTL but were also capable of efficiently activating an antigen-specific CTL response. Interestingly, the immunogenicity of these BL cells was not affected by the significantly down-regulated expression of adhesion molecules such as LFA1 alpha, LFA1 beta and LFA3. These findings suggest that resistance of tumour cells to CTL-mediated immune control can be reversed if the relevant peptide epitopes are appropriately presented on the cell surface.
Khanna
R
R
Queensland Institute of Medical Research, Bancroft Centre, Herston, Australia.
Burrows
S R
SR
Argaet
V
V
Moss
D J
DJ
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000502:physiology*; D000956:Antigens, Viral / Q000378:metabolism; D001483:Base Sequence; D001692:Biological Transport; D002051:Burkitt Lymphoma / Q000276:immunology*; D002352:Carrier Proteins / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000502:physiology*; D000939:Epitopes / Q000378:metabolism*; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D008969:Molecular Sequence Data; D021382:Protein Sorting Signals / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D000956:Antigens, Viral; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D000939:Epitopes; D021382:Protein Sorting Signals; C073119:TAP1 protein, human; C071692:TAP2 protein, human