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Carbohydrate antigens rarely provide target epitopes for cytotoxic T lymphocytes (CTL). Disialoganglioside GD2 is a glycolipid expressed at high levels in human tumors and a small group of murine lymphomas (EL4, RBL5, RMA, RMA-S, A13, and BALBRVE). Immunization of C57B1/6 mice with irradiated EL4 cells stimulated a specific CTL response and protected these animals from engraftment of EL4 lymphoma. The CTL activity resided in the CD4-CD8+ population, was dependent on T cell receptor alpha/beta, and was not removed by anti-natural killer cell immunoabsorption, but was restricted to GD2 and H-2b bearing targets. CTL activity could be completely inhibited by GD2-oligosaccharide-specific monoclonal antibodies and their F(ab')2 fragments, but not by immunoglobulin G3 myelomas or antibodies against GD3 or GM2. Solub…