Thymus-derived lymphocytes serve as the principal cellular regulators of immune responses communicating with other cell types via soluble mediators called lymphokines. Activation of T cells is accompanied by lymphokine release but cells differ both in the range of mediators they can produce and the activation signals capable of eliciting their production. Our purpose is to elucidate both extrinsic and intrinsic regulation of lymphokine release. A model system using a large panel of well-characterized human T lymphocyte clones will be employed to test the hypothesis that the nature of the antigenic signal delivered to a heterogeneous population of cells determines, in part, the type of lymphokines produced and that T cells committed to different antigenic determinants also differ in the lymphokines they are capable of secreting. Mediators regulating myelopoietic progenitor cell (colony stimulating factor), B cell (B cell growth factor), T cell (interleukin-2) and macrophage (interferon-gamma) growth and differentiation will be studied. As a means of identifying the inter- and intracellular signals required for lymphokine release, interferon-gamma (IFN-gamma) production by cloned human T cells will serve as a model. IFN-gamma production is selectively inhibited by certain bacterial products. Thus, determining the mechanism by which these factors suppress IFN-gamma release should yield valuable information on the signals leading to lymphokine production by T cells. Of particular interest will be accessory cell and interleukin requirements and intracellular messengers (e.g., calcium mobilization and protein phosphorylation). Results of these studies should not only provide valuable information on the activation signals required for lymphokine production by T cells, but should also suggest means of controlling T cell functions by pharmacologic or immunologic intervention (e.g., appropriate construction of synthetic vaccines). Since IFN-gamma, in particular, is known to be a potent activator of macrophages and natural killer cells, both of which are important in limiting tumor growth and metastases, information derived from this project will have direct relevance to anti-tumor immunity.
