This proposal focuses on the regulation of the growth and function of cloned antitumor lymphocytes. The experiments over the last three years have demonstrated that lytic activity of a population of cells varies over a continuum of lytic efficiency at the level of individual cells rather than by alteration of the ratio of highly lytic/non lytic cells. The only soluble factor necessary for the regulation of an individual cell's lytic capacity is interleukin 2 (IL-2). The mechanism of IL-2 regulation appears to be through a general stimulation of protein synthesis rather than through the selective regulation of relevant genes. In addition we have found evidence for the differential regulation of lymphocyte sub classes by different lymphokines. We will pursure these studies with clonal models of different lymphocyte sub classes. In addition we will pursue similar studies with selected normal lymphocytes at different states of activation. Based on experiments with clones that cross react with multiple antigens we have developed a model for the differential regulation of growth and lytic responses by the avidity of the interaction between the CTL and an antigen bearing cell. Thus a weak interaction is optimal for stimulation of proliferation while stronger interactions are optimal for the stimulation of a lytic response. This differential regulation of responses allows for antigen presentation by weak antigenic species within the lymphoid system and limits lytic activity to the tumor, infection or graft site. In addition factors such as interferon that regulate class I antigen expression on the target cell produce an increased effectiveness of the lytic process at the anatomical site of attack. Finally we demonstrate that the antigen specific interaction can have a negative as well as a positive influence on CTL growth. This negative effect appears to be a direct effect on the responding cell itself rather than a secondary effect of soluble agents. The negative effect on growth is through an antigen-induced non responsiveness to IL-2. An understanding of the mechanism of an antigen induced block in proliferation may yield important information about the nature of one form of the induction of tolerance.
