Immediate effects of reversible HTLV-1 tax function: T-cell activation and apoptosis.
The tax protein of Human T-cell leukemia virus type 1 (HTLV-1) is important for the transforming properties of this virus in vitro and is considered to be responsible for the early stages of leukemogenesis in infected hosts. To address the early consequences of HTLV-1 tax function, we have constructed fusion proteins containing tax sequence either aminoterminal (taxER) or carboxy-terminal (ERtax) of the hormone binding domain of the human estrogen receptor (ER). Addition of estrogen or the antagonist hydroxytamoxifen to Jurkat T-cells expressing these constructs led to the trans-activation or responsive promoters and upregulation of cell surface markers CD28, CD69 and CD5 but not CD25 (IL2R-alpha subunit) or B7 (ligand for CD28). Additional stimulation of the T-cell receptor CD3 complex, led to the upregulation of CD25. B7 was upregulated by concomittent activation of ERtax and CD3 or CD28 pathways. These events were in part reversible upon withdrawal of hormone and inactivation of ERtax. Severe inhibition of proliferation, and apoptosis was observed with cells which had been subjected to short term (3 days) activation of the tax fusion proteins and the CD3 complex. Induction of ERtax activity for longer than 3 days promoted cell death independently of CD3 stimulation. Co-stimulation through the CD28 cell surface molecule did not suppress induction of apoptosis.
Department of Tumor Immunology, German Cancer Research Center, Heidelberg.
K
K
Chlichlia
G
G
Moldenhauer
P T
PT
Daniel
M
M
Busslinger
L
L
Gazzolo
V
V
Schirrmacher
K
K
Khazaie
D017209:Apoptosis; D018106:CD28 Antigens / Q000096:biosynthesis; D017252:CD3 Complex / Q000096:biosynthesis; D002455:Cell Division; D004967:Estrogens / Q000494:pharmacology; D005434:Flow Cytometry; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation; D011960:Receptors, Estrogen / Q000235:genetics; D011994:Recombinant Proteins; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D018106:CD28 Antigens; D017252:CD3 Complex; D004967:Estrogens; D016356:Gene Products, tax; D011960:Receptors, Estrogen; D011994:Recombinant Proteins