Activation induces apoptosis in Herpesvirus saimiri-transformed T cells independent of CD95 (Fas, APO-1).
Signaling via the T cell receptor (TCR)/CD3 complex of pre-activated T cells induces apoptosis. Such an activation-induced cell death (AICD) is thought to play an important role in the regulation of cellular immune responses. In this study we analyzed pathways of AICD by using human T cells transformed by Herpesvirus saimiri. These growth-transformed T cells show the phenotype of activated mature T cells and continue to express a functionally intact TCR. We show that human H. saimiri-transformed T cell clones readily undergo cell death upon signaling via the TCR/CD3 complex or via phorbol 12-myristate 13-acetate (PMA) + ionomycin. The AICD in H. saimiri-transformed T cells was detectable a few hours after activation and it was not affected by the presence of interleukin (IL)-2 or by anti-CD4 cross-linking. However, AICD required tyrosine phosphorylation, since it could be blocked by herbimycin A. Cyclosporin A (CsA) did not block the development of AICD, but other consequences of activation in H. saimiri-transformed T cells like the production of interferon-gamma. Surprisingly, the development of AICD was not reduced by neutralizing antibodies to tumor necrosis factor (TNF)-alpha or blocking antibodies directed to CD95 (Fas, APO-1), although H. saimiri-transformed T cells were sensitive to CD95 ligation. To confirm that this form of AICD is really independent of CD95, we have established an H. saimiri-transformed T cell line from a patient with a homozygous deletion in the CD95 gene. This CD95-deficient T cell line was as sensitive to AICD as other CD95-expressing H. saimiri-transformed T cells. In conclusion, we describe here a type of AICD in H. saimiri-transformed T cells that is independent of CD95 and TNF-alpha, not sensitive to CsA, but requires tyrosine phosphorylation. This system should be useful for the investigation of CD95-independent forms of AICD.
Bröker
B M
BM
Bernhard-Nocht-Institut, Hamburg, Germany.
Kraft
M S
MS
Klauenberg
U
U
Le Deist
F
F
de Villartay
J P
JP
Fleckenstein
B
B
Fleischer
B
B
Meinl
E
E
D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D016572:Cyclosporine / Q000494:pharmacology; D006567:Herpesvirus 2, Saimiriine / Q000276:immunology*; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects; D010766:Phosphorylation; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism / Q000502:physiology*
D008024:Ligands; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D014443:Tyrosine; D016572:Cyclosporine