The ability of three cultured mouse tumor lines to stimulate a cytotoxic response in 5-day cultures of allogeneic lymph node cells was studied with a 5"Cr release assay. Two lines of mesenchymal origin, P815 and EL-4, were found to be highly stimulatory, whereas the third cell line, CaDZ, a mammary wand epithelial tumor, did not stimulate over a wide range of cell concentration. CaD2 cells were shown to contain major antigens similar to those of P815 cells by the specific lysis of both cells by lymphocytes activated to H-2d-bearing peritoneal cells. UV-irradiated P815-cells, like y-irradiated CaD2 cells, did not stimulate a cytotoxic response, but both cell lines were found to stimulate a full and specific response to allogeneic lymph node cells if these mixed cultures were supplemented with a stipernatant harvested from concanavalin A-stimulated spleen cells.We have postulated that a specialized stimulator cell designated as S+ is required for T cell activation (1). Antigen presented on the surface of the S+ cell should facilitate the interaction of the stimulator cell with the potentially responsive T cell clone. Thus, T cell activation was thought to require antigen recognition in conjunction with the delivery of an inductive stimulus from the S+ cell. The production of the inductive agent by the stimulator cell or its delivery to the responsive T cell must usually require metabolic activity of the S+ cell (refs. 2