Discerning regulation of cis- and trans-presentation of CD8+ T-cell epitopes by EBV-encoded oncogene LMP-1 through self-aggregation.
Activation of the nuclear factor-kappaB pathway by Epstein-Barr virus-encoded latent membrane protein-1 (LMP-1) leads to an up-regulation of the major histocompatibility complex class I antigen-processing pathway. Paradoxically, LMP-1 itself induces a subdominant CD8+ T-cell response and appears to have evolved to avoid immune recognition. Here we show that, although expression of LMP-1 in human cells dramatically enhanced the trans-presentation of CD8+ T-cell epitopes, cis-presentation of LMP-1-derived epitopes was severely impaired. Testing of a series of LMP-1 mutants revealed that deletion of the first transmembrane domain of LMP-1, which prevented self-aggregation, significantly enhanced cis-presentation of T-cell epitopes from this protein, whereas it lost its ability to up-regulate trans-presentation. Interestingly, we also found that cis-presentation of LMP-1 epitopes was rescued by blocking the proteasome function. Taken together, these results delineate a novel mechanism of immune evasion, which renders a virally encoded oncogene inaccessible to the conventional major histocompatibility complex class I pathway limiting its cis-presentation to effector cells.
Smith
Corey
C
Australian Centre for Vaccine Development and Tumour Immunology Laboratory, Division of Immunology, Queensland Institute of Medical Research, Brisbane, Australia.
Wakisaka
Naohiro
N
Crough
Tania
T
Peet
Jesse
J
Yoshizaki
Tomokazu
T
Beagley
Leone
L
Khanna
Rajiv
R
D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002461:Cell Line, Transformed; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000276:immunology; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000473:pathology; D009303:Nasopharyngeal Neoplasms / Q000276:immunology* / Q000473:pathology; D010446:Peptide Fragments / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055503:Protein Multimerization; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000473:pathology; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology*
C508151:EBNA-3A antigen; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D018984:Epitopes, T-Lymphocyte; D019309:Epstein-Barr Virus Nuclear Antigens; D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments; D014763:Viral Matrix Proteins; D007371:Interferon-gamma; D046988:Proteasome Endopeptidase Complex