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GD3, an Overexpressed Tumor-Derived Ganglioside, Mediates the Apoptosis of Activated but not Resting T Cells

¹ Department of Immunology, Lerner Research Institute and ² Experimental Therapeutics, Taussig Cancer Center, Cleveland Clinic, Cleveland, Ohio and ³ Molecular Medicine Division, Bose Institute, Kolkata, India

Requests for reprints: Charles Tannenbaum, Department of Immunology/NE4-308, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195. Phone: 216-445-0575; Fax: 216-444-9329; E-mail: tannenc{at}ccf.org or James H. Finke, Department of Immunology/NE4-307, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195. Phone: 216-445-5186; Fax: 216-444-9329; E-mail: finke{at}ccf.org.

Key Words: Apoptosis • GD3 • T lymphocytes • Tumor Immunity

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-B–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. [Cancer Res 2009;69(7):3095–104]