Inhibition of apoptosis in T cells expressing human T cell leukemia virus type I Tax.
This study set out to determine whether T cell dysfunction associated with HTLV-I led to increased sensitivity of infected cells to apoptosis or, owing to their potential to develop ATL, if infected cells would become resistant to this process. To test this hypothesis we utilized the monoclonal antibody anti-APO-1, which has been demonstrated to induce apoptosis in human T cells. Human T cell lines expressing HTLV-I showed reduced susceptibility to anti-APO-1-induced apoptosis despite expression of high levels of cell surface APO-1. Cell-free supernatant of the Tax-expressing cell line C8166 and heat-inactivated supernatant of the HTLV-I-producing cell line MT2 transferred increased resistance to anti-APO-1 to susceptible Jurkat T cells. Susceptible T cells transfected with an HTLV-I Tax-expressing vector or treated with soluble Tax protein became less susceptible to anti-APO-1-induced cell death. Furthermore, primary human lymphocytes treated with soluble Tax were less susceptible to apoptosis induced by anti-APO-1. The protective effect of Tax in T cell lines and primary human lymphocytes was reversed by the addition of anti-Tax antibodies. Anti-APO-1-induced apoptosis was also found to be inhibited in Jurkat cells by the induction of protein kinase C (PKC) with 12-O-tetradecanoylphorbol-13-acetate (TPA). Resistance to apoptosis conferred by HTLV-I Tax and an active PKC pathway may be factors contributing to the survival of dysregulated HTLV-I-infected T cells prone to the development of adult T cell leukemia.
Copeland
K F
KF
Laboratory of Viral Pathogenesis, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
Haaksma
A G
AG
Goudsmit
J
J
Krammer
P H
PH
Heeney
J L
JL
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000954:Antigens, Surface / Q000032:analysis / Q000096:biosynthesis / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D004790:Enzyme Induction; D015870:Gene Expression; D016356:Gene Products, tax / Q000096:biosynthesis*; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D011493:Protein Kinase C / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology* / Q000821:virology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D019014:fas Receptor
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D016356:Gene Products, tax; D019014:fas Receptor; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate