ICE-proteases mediate HTLV-I Tax-induced apoptotic T-cell death.
The Tax protein of Human T-cell leukemia virus type 1 (HTLV-1) is important for the T-cell immortalizing properties of this virus in vitro and is considered to be responsible for the early stages of leukemogenesis in infected hosts. Tax can upregulate expression of TNF-alpha and TNF-beta, as well as potentiate apoptosis in activated T-cells and in serum starved murine fibroblasts. To examine the role of CD95 (APO-1/Fas) and ICE-proteases in Tax-mediated active T-cell death, Jurkat T cells expressing (APO(S)) or lacking (APO(R)) cell surface expression of CD95 (APO-1/Fas) were genetically modified to express hormone-inducible HTLV-1 Tax constructs. Hormone-inducible action of Tax alone was sufficient to promote programmed cell death in CD95-expressing Jurkat T-cell clones. In contrast, clones lacking CD95 surface expression were resistant to the antiproliferative action of Tax. Both APO(S) and APO(R) clones exhibited Tax-dependent upregulation of CD95 ligand and TNF-alpha. Blocking experiments suggested that while the apoptotic action of Tax critically required ICE-protease function it was largely independent of cell surface interaction of CD95 ligand or TNF-alpha with their corresponding receptors. These observations strongly implicate ICE-proteases in Tax-induced T-cell death, and suggest a possible involvement of CD95 in this process.
Chlichlia
K
K
Tumorimmunology Program, German Cancer Research Center.
Busslinger
M
M
Peter
M E
ME
Walczak
H
H
Krammer
P H
PH
Schirrmacher
V
V
Khazaie
K
K
D017209:Apoptosis; D020170:Caspase 1; D002999:Clone Cells; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D016356:Gene Products, tax / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D010455:Peptides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology*
D015853:Cysteine Proteinase Inhibitors; D016356:Gene Products, tax; D010455:Peptides; D003546:Cysteine Endopeptidases; D020170:Caspase 1