Vesicles released by activated T cells induce both Fas-mediated RIP-dependent apoptotic and Fas-independent nonapoptotic cell deaths.
Activated T cells secrete Fas ligand (FasL)-containing vesicles (secreted vesicles) that induce death of target cells. We provide evidence that secreted vesicles from culture supernatants (Csup) of various origins are able to generate both Fas-dependent apoptotic and Fas-independent, nonapoptotic cell death. In the absence of Fas, the nonapoptotic, Fas-independent pathway could still induce cell death. In contrast to RIP-independent classical Fas-induced cell death triggered by cross-linked or membrane-bound FasL, CSup-derived stimuli-induced apoptosis exhibited unique molecular and enzymatic characteristics. It could be partially inhibited by blocking cathepsin D enzyme activity and required the presence of RIP. Whereas stimulation with CSup, derived from both FasL-overexpressing Jurkat cells and PBMC, could induce cell death, the requirements for Fas-associated death domain protein and caspase-9 were different between the two systems. Our study highlights an important distinction between cell contact-mediated and secreted vesicle-generated activation-induced cell death and also demonstrates that the type of the secreted vesicles can also modify the cell death route. We propose that besides cell-to-cell interaction-mediated Fas triggering, stimuli induced by secreted vesicles can mediate important additional cell death signals regulating activation-induced cell death under physiological conditions.
Immunology Research Group, Hungarian Academy of Sciences, University Eötvös Lorand, H-1117 Budapest, Hungary.
Gábor
G
Koncz
Anikó
A
Hancz
Krittalak
K
Chakrabandhu
Péter
P
Gogolák
Krisztina
K
Kerekes
Eva
E
Rajnavölgyi
Anne-Odile
AO
Hueber
D017209:Apoptosis / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D016923:Cell Death / Q000276:immunology; D002471:Cell Transformation, Neoplastic / Q000276:immunology; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D003564:Cytidine Deaminase / Q000502:physiology; D022162:Cytoplasmic Vesicles / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D003601:Cytotoxicity Tests, Immunologic; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D019014:fas Receptor / Q000502:physiology*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D017077:Culture Media, Conditioned; C491901:FAS protein, human; D019014:fas Receptor; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase