It is now clear that antigen presenting cells (APC) do not distinguish between self and foreign proteins and that self-proteins are constitutively processed and presented in vivo. Thus, the T cell has been delegated the responsibility of the self/nonself discrimination, through the process of tolerance. Humans and mice express approximately 50,000 different proteins, and each one has different characteristics and properties. The tolerance mechanisms have to be able to deal efficiently with this vast array of different self-antigens. Previous studies have only indirectly been able to examine the tolerance to self-proteins in vivo, since the expression of a defined antigen was not able to be controlled. We propose to develop a transgenic mouse system in which a chimeric protein composed of hen egg-white lysozyme, and a fragment of self hemoglobin, is expressed using a binary expression system. This system, which uses bacterial transactivator LAP267, will allow us to completely control the expression of this neo-self protein at different times in vivo. Using this system, we will be able to definitively ascertain the relationship between the expression of a self-protein and self-tolerance. In addition to deletion of T cells in the thymus, peripheral mechanisms are also involved in T cell tolerance. Using a substituted analog of the Hb(64-76) determinant, we showed that the Th2 clone, 2.102, could be partially activated. This peptide, Asp73, was able to induce IL-4 production, but no proliferation. This novel and important finding suggested that the T cell receptor was able to receive different signals, and depending upon their quality and quantity, various intracellular pathways could be activated. In this renewal application, we propose to continue our studies on partial T cell activation. These studies focus on two interrelated areas, tolerance induction, and the mechanisms involved in partial signaling. We have been able to tolerize a Th2 clone, using fixed APC. We have also been able to tolerize a Th1 clone using a non- stimulatory analog peptide. We propose to characterize these two different tolerance induction systems, especially in comparison to the extensively studied Th1 anergy system which involves fixed APC. We will also further examine our observation that analog peptides can act as T cell receptor antagonists, and inhibit either antigen or bacterial superantigen response. Overall, these studies will provide important insights into the process of partial T cell activation and how it relates to the functioning of a T cell.
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