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 pore formation, induction of apoptosis by the Fas ligand, or both. It has been demonstrated that depolarized neurons can be induced to express major histocompatibility complex (MHC) class I antigens by interferon-gamma. Evidence for antigen-dependent CTL-mediated killing was obtained by transfecting neurons with MHC class I cDNA. The present study was designed to investigate the mechanisms of killing of cerebellar granule neurons depolarized by high K+ concentrations and thereby inducible for MHC class I antigen expression. We found that neurons express only low levels of Fas (APO-1/CD95) and are resistant to Fas ligand-mediated killing even when pretreated with cytokines. However, granules extracted 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.
Rensing-Ehl
A
A
Department of Internal Medicine, University Hospital, Zürich, Switzerland.
Malipiero
U
U
Irmler
M
M
Tschopp
J
J
Constam
D
D
Fontana
A
A
D000818:Animals; D003602:Cytotoxicity, Immunologic; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000276:immunology*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology*
D015395:Histocompatibility Antigens Class I; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D019014:fas Receptor; D054353:Perforin; D007371:Interferon-gamma