MYC overexpression imposes a nonimmunogenic phenotype on Epstein-Barr virus-infected B cells.
Lymphoblastoid cell lines, generated by immortalization of normal B cells by Epstein-Barr virus (EBV) in vitro, have strong antigen-presenting capacity, are sensitive to EBV-specific cytotoxic T cells, and are highly allostimulatory in mixed lymphocyte culture. By contrast, EBV-positive Burkitt lymphoma (BL) cells are poor antigen presenters, are not recognized by EBV-specific cytotoxic T cells, and are poorly allostimulatory, which raises the question of whether immunological pressure exerted during BL pathogenesis in vivo has selected for a 'nonimmunogenic' tumor phenotype. The present work addresses this question by examining the immunogenicity/antigenicity of cell lines, generated by conversion of a conditionally immortalized lymphoblastoid cell line to permanent growth independent of EBV-latent proteins by introduction of a constitutively active or tetracycline-regulated c-myc gene (A1 and P493-6 cells, respectively). Compared with its parental lymphoblastoid cell line, A1 cells showed many of the features of the nonimmunogenic BL phenotype, namely poor allostimulatory activity, poor antigen-presenting function associated with impaired proteasomal activity, down-regulation of peptide transporter, reduced HLA class I expression, and an inability to present endogenously expressed EBV-latent proteins to cytotoxic T cells. P493-6 cells, when grown in the presence of estrogen with the exogenous c-myc gene switched off, were strongly immunogenic. The cells had lost their immunogenic potential, however, when grown on a c-myc-driven proliferation program in the absence of estrogen. Deregulation of c-myc, a step central to the development of uncontrolled BL cell growth in vivo, can thus impose a nonimmunogenic phenotype on proliferating human B cells in the absence of any immune pressure.
Staege
Martin S
MS
Institut für Klinische Molekularbiologie und Tumorgenetik, GSF-Forschungszentrum für Umwelt und Gesundheit, Marchioninistrasse 25, D-81377 München, Germany.
Lee
Steven P
SP
Frisan
Teresa
T
Mautner
Josef
J
Scholz
Siegfried
S
Pajic
Alexander
A
Rickinson
Alan B
AB
Masucci
Maria G
MG
Polack
Axel
A
Bornkamm
Georg W
GW
D017951:Antigen Presentation; D001402:B-Lymphocytes / Q000276:immunology* / Q000821:virology; D019309:Epstein-Barr Virus Nuclear Antigens / Q000502:physiology; D005822:Genetic Vectors; D015234:HLA-A Antigens / Q000032:analysis; D059870:HLA-A11 Antigen; D015793:HLA-B7 Antigen / Q000032:analysis; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics; D014764:Viral Proteins
C402641:EBNA-2 protein, Human herpesvirus 4; D019309:Epstein-Barr Virus Nuclear Antigens; D015234:HLA-A Antigens; D059870:HLA-A11 Antigen; D015793:HLA-B7 Antigen; D016271:Proto-Oncogene Proteins c-myc; D014764:Viral Proteins