NEURONS INDUCED TO EXPRESS MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I ANTIGEN ARE KILLED VIA THE PERFORIN AND NOT THE FAS (APO-1 CD95) PATHWAY/

Cytotoxic T lymphocytes (CTL) kill target cells by perforin-mediated p ore formation, induction of apoptosis by the Fas ligand, or both. It h as been demonstrated that depolarized neurons can be induced to expres s major histocompatibility complex (MHC) class I antigens by interfero n-gamma. Evidence for antigen-dependent CTL-mediated killing was obtai ned by transfecting neurons with MHC class I cDNA. The present study w as designed to investigate the mechanisms of killing of cerebellar gra nule neurons depolarized by high K+ concentrations and thereby inducib le for MHC class I antigen expression. We found that neurons express o nly low levels of Fas (APO-1/CD95) and are resistant to Fas ligand-med iated killing even when pretreated with cytokines. However, granules e xtracted from CTL as well as purified perforin induce almost complete lysis of neurons. These data suggest that CTL-mediated elimination of neurons involves the perforin, but not the Fas pathway of target cell killing.