Cytotoxic T cells specifically induce Fas on target cells, thereby facilitating exocytosis-independent induction of apoptosis.
Cytotoxic T (Tc) cells deficient in perforin lyse Fas-negative targets after lengthy incubation periods. This process is independent of granzymes, and killing occurs via the Fas pathway for the following reasons. Interaction of perforin-deficient Tc cells with Fas-negative targets leads to an up-regulation of Fas that is dependent on Ag recognition, de novo synthesis, and transport of proteins to the target cell surface. Treatment of effectors with brefeldin A, but not with the exocytosis inhibitor concanamycin, inhibited this process. Lysis of targets is inhibited by anti-Fas Abs, soluble mouse Fas-Fc, and the caspase-cascade inhibitor, crm-A. Targets from Fas-mutant lpr mice are refractory to lysis, and Tc cells from mice deficient in Fas- and perforin-mediated lysis do not lyse Fas-negative targets. The possible relevance of this exocytosis-independent cytolytic process in the regulation of T cell activity and control of pathogens is discussed.
Simon
M M
MM
Max Planck Institut für Immunbiologie, Freiburg, Germany.
Waring
P
P
Lobigs
M
M
Nil
A
A
Tran
T
T
Hla
R T
RT
Chin
S
S
Müllbacher
A
A
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D020126:Brefeldin A / Q000494:pharmacology; D018920:Coculture Techniques; D003513:Cycloheximide / Q000494:pharmacology; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000235:genetics; D003609:Dactinomycin / Q000494:pharmacology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D005089:Exocytosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D053804:Granzymes; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007519:Isoantigens / Q000235:genetics / Q000276:immunology; D007739:L Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D007939:Leukemia L1210 / Q000276:immunology / Q000473:pathology; D018942:Macrolides; D012515:Mast-Cell Sarcoma / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D019014:fas Receptor / Q000096:biosynthesis* / Q000235:genetics
D000900:Anti-Bacterial Agents; D018984:Epitopes, T-Lymphocyte; D007166:Immunosuppressive Agents; D007519:Isoantigens; D018942:Macrolides; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D019014:fas Receptor; D054353:Perforin; D003609:Dactinomycin; D020126:Brefeldin A; C036978:concanamycin A; D003513:Cycloheximide; C509213:GZMB protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases; C509212:GZMA protein, human