title: GD3, an overexpressed tumor-derived ganglioside, mediates the apoptosis of activated but not resting T cells.
abstract: We previously elucidated an important role for gangliosides in renal cell carcinoma-mediated T lymphocyte apoptosis, although the mechanism by which they mediated lymphocyte death remained unclear. Here, we show that when added in purified form, GD3 is internalized by activated T cells, initiating a series of proapoptotic events, including the induction of reactive oxygen species (ROS), an enhancement of p53 and Bax accumulation, an increase in mitochondrial permeability, cytochrome c release, and the activation of caspase-9. GD3-induced apoptosis of activated T cells was dose dependent and inhibitable by pretreating the lymphocytes with N-acetylcysteine, cyclosporin A, or bongkrekic acid, emphasizing the essential role of ROS and mitochondrial permeability to the process. Ganglioside-induced T-cell killing was associated with the caspase-dependent degradation of nuclear factor-kappaB-inducible, antiapoptotic proteins, including RelA; this suggests that their loss is initiated only after the cascade is activated and that their disappearance amplifies but not triggers GD3 susceptibility. Resting T cells did not internalize appreciable levels of GD3 and did not undergo any of the proapoptotic changes that characterize activated T lymphocytes exposed to the ganglioside. RelA overexpression endows Jurkat cells with resistance to GD3-mediated apoptosis, verifying the role of the intact transcription factor in mediating protection from the ganglioside.
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Gaurisankar
authors.initials: G
authors.lastname: Sa
authors.forename: Tanya
authors.initials: T
authors.lastname: Das
authors.forename: Christina
authors.initials: C
authors.lastname: Moon
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Hilston
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Rayman
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
authors.forename: Charles S
authors.initials: CS
authors.lastname: Tannenbaum
authors.forename: James H
authors.initials: JH
authors.lastname: Finke
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000473:pathology; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D045304:Cytochromes c / Q000276:immunology / Q000378:metabolism; D005732:Gangliosides / Q000276:immunology* / Q000493:pharmacokinetics; D005909:Glioblastoma / Q000276:immunology / Q000473:pathology; D006801:Humans; D019169:Jurkat Cells; D007680:Kidney Neoplasms / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D051336:Mitochondrial Membranes / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D000975:Antioxidants; D061945:Caspase Inhibitors; D005732:Gangliosides; D017382:Reactive Oxygen Species; C026226:ganglioside, GD3; D045304:Cytochromes c; C505530:CASP8 protein, human; D053181:Caspase 8; D053453:Caspase 9; D000111:Acetylcysteine