T lymphocytes play an integral role in both cellular and humoral immune responses, carrying out direct effector functions such as cytolysis as well as mediating regulatory functions via secreted lymphokines. T cell activation antigen can be defined only in operational terms: development of functional activity, lymphokine production, or proliferation. The antigen receptor accounts for the specificity of T cell responses. Antigenic stimulation induces lymphokine secretion, including interleukin 2 (IL-2), and also causes an increase in the number of cell surface receptors for IL-2 which, in turn, augments the proliferative response produced by IL-2. The biochemical events which follow stimulation of T cells have not been fully characterized. T cell responses are modulated in a variety of ways. IL-2 has a profound immunoregulatory effect on the cell which produces it: When cells which secrete IL-2 are exposed to IL-2, they become unresponsive to antigen. Gamma interferon acts on macrophages to increase expression of class II major histocompatibility antigens which are required for effective antigen presentation. Resting macrophages secrete apoprotein E which has profound inhibitory immunoregulatory activity; this secretion is reduced when macrophages are stimulated. Thus, there are several feedback pathways that can influence T cell responses. We intend to characterize the cellular and biochemical processes which are associated with activation of T lymphocytes. In particular, we want to distinguish between those events that are initiated by stimulation with antigen and those that are induced by lymphokines such as IL-2. We also intend to characterize the processes involved in the negative regulation of T cell responses. In particular, we want to determine the basis for unresponsiveness to antigen which is induced when cloned murine T cells are exposed to IL-2. We also want to determine the role of apoprotein-E, produced by macrophages, in the regulation of the response of T cells. In these studies, we will use cloned T cells, fixed antigen-presenting cells, monoclonal antibodies, and lymphokines produced by recombinant DNA technology. Thus, discriminating model systems are available for studying the metabolic events induced by specific stimuli.
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