This proposal is based on the recent discovery that murine helper/inducer T cells vary in the lymphokines they secrete and utilize as autocrine growth factors in response to receptor- mediated stimulation. The theme of the project is to define the biologic significance of the selective production of IL2 or BSF1 (IL4) by different T cell subsets. The rationale for postulated differences between these T cell subsets is based on the known functions of various lymphokines and, therefore, provides a more physiologic parameter for distinguishing cell types than surface phenotype or other markers. The main goals of this research are as follows: 1. To establish clonal heterogeneity in helper/inducer T cells by generating a large panel of clones reactive with the same antigen + Ia combinations and defining the profiles of lymphokines secreted (BSF1, IL2, IFN gamma). Clones that fall into distinct subsets will be compared for: 1) function, i.e. help for resting and activated B lymphocytes, and macrophage activation, and ii) activation requirements, with emphasis on recognition of antigen on B and non-B antigen presenting cells and IL1 dependence. Preliminary experiments have established the necessary assays, suggested striking differences between BSF1- and IL2 + IFN gamma-producing clones, and indicated why such differences are consistent with the biologic effects of the various lymphokines. 2. The presence of subsets varying in lymphokine secretion, and their correlation with biologic responses, will be analyzed in unselected (bulk) populations of normal and immune T cells, in order to confirm concepts developed with cloned lines. 3. Cloned T cell lines will be used to study the mechanisms of action of lymphokines, including: i) intracellular biochemical alterations, ii) the role of costimulators such as IL1 in altering lymphokine receptor expression or providing signals for cell growth, and iii) the effect of antigen receptor-mediated stimulation on lymphokine production and commitment to proliferative responses. 4. Other long term goals include the development of BSF1 indicator lines, antibodies specific for BSF1 receptors, and phenotypic markers for T cell subsets varying in profiles of lymphokine secretion. This project provides a novel approach to studying T cell heterogeneity and will help to resolve issues about T cell responses to receptor-mediated stimuli that are largely unexplored, to date.
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