AbstractSignaling 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 byHerpesvirus 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 humanH. 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 inH. 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 inH. saimiri‐transformed T cells like the production of interferon‐γ. Surprisingly, the development of AICD was not reduced by neutralizing antibodies to tumor necrosis factor (TNF)‐α or blocking antibodies directed to CD95 (Fas, APO‐1), althoughH. saimiri‐transformed T cells were sensitive to CD95 ligation. To confirm that this form of AICD is really independent of CD95, we have established anH. 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‐expressingH. saimiri‐transformed T cells. In conclusion, we describe here a type of AICD inH. saimiri‐transformed T cells that is independent of CD95 and TNF‐α, not sensitive to CsA, but requires tyrosine phosphorylation. This system should be useful for the inv
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