title: Activation-induced cell death of human T-cell subsets is mediated by Fas and granzyme B but is independent of TNF-alpha.
abstract: Human primary effector T cells were analyzed for their susceptibility to anti-CD3-induced activation-induced cell death (AICD). Th1 and Tc1 cells were more susceptible to AICD than their type 2 counterparts. Type 1 and type 2 subsets were also found to be differentially susceptible to CD95-mediated apoptosis, although cell-surface expression of CD95 and CD95L was at similar levels on all subsets. A role for CD95 in AICD was confirmed by the addition of anti-CD95L antibodies that partially abrogated AICD. Residual apoptosis could not be accounted for by TNF-alpha/TNFR interactions because although type 1 cells secreted more TNF-alpha than type 2 cells, the addition of TNFR:Fc fusion protein did not inhibit AICD. Instead, a reduction in AICD was observed in the presence of EGTA or concanamycin A. The inhibition of apoptosis by a granzyme B inhibitor z-AAD-CMK in Tc1 cells further indicated an involvement of the granule exocytosis mechanism in AICD.
authors.affiliation: Guy's, King's and St. Thomas' School of Medicine, Rayne Institute, London, United Kingdom.
authors.forename: P
authors.initials: P
authors.lastname: Gorak-Stolinska
authors.forename: J P
authors.initials: JP
authors.lastname: Truman
authors.forename: D M
authors.initials: DM
authors.lastname: Kemeny
authors.forename: A
authors.initials: A
authors.lastname: Noble
mesh_terms: D000328:Adult; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002118:Calcium; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D002614:Chelating Agents / Q000494:pharmacology; D003594:Cytoplasmic Granules / Q000378:metabolism; D004533:Egtazic Acid / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000068800:Etanercept; D005089:Exocytosis; D053222:Fas Ligand Protein; D053804:Granzymes; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000378:metabolism; D008213:Lymphocyte Activation; D018942:Macrolides; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D016853:Muromonab-CD3 / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019014:fas Receptor / Q000502:physiology*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000900:Anti-Bacterial Agents; D061945:Caspase Inhibitors; D002614:Chelating Agents; D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007074:Immunoglobulin G; D007376:Interleukin-2; D018942:Macrolides; D008562:Membrane Glycoproteins; D016853:Muromonab-CD3; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C440223:Z-Ala-Ala-Asp-chloromethylketone; D019014:fas Receptor; D018664:Interleukin-12; D015847:Interleukin-4; D004533:Egtazic Acid; C036978:concanamycin A; D007371:Interferon-gamma; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D000068800:Etanercept; D002118:Calcium