TCR engagement regulates differential responsiveness of human memory T cells to Fas (CD95)-mediated apoptosis

In this work, we have tried to establish whether human memory T cells may b e protected from Fas (CD95)-induced apoptosis when correctly activated by A g, and not protected when nonspecifically or incorrectly activated. In part icular, we wanted to investigate the molecular mechanisms that regulate the fate of memory T cells following an antigenic challenge, To address this i ssue, we chose an experimental system that closely mimics physiological T c ell activation such as human T cell lines and clones specific for viral pep tides or alloantigens. We demonstrate that memory T cells acquire an activa tion-induced cell death (AICD)-resistant phenotype when TCRs are properly e ngaged by specific Ag bound to MHC molecules, Ag concentration and costimul ation are critical parameters in regulating the protective effect. The anal ysis of the mechanisms involved in the block of CD95 signal transduction pa thways revealed that the crucial events are the inhibition of CD95-associat ed IL-1 beta-converting enzyme (ICE)-like protease (FLICE) activation and p oly(ADP)-ribose polymerase cleavage, and the mRNA expression of FLICE-like inhibitory protein. Furthermore, we have observed that TCR-mediated neosynt hesis of FLICE-like inhibitory protein mRNA is suppressed either by protein tyrosine kinase inhibitors or cyclosporin A, In conclusion, the present an alysis of the effects of TCR triggering on the regulation of AICD suggests that AICD could be inhibited in human memory T cells activated in vivo by a foreign Ag, but may become operative when the Ag has been cleared.