This is a proposal to test a novel concept in self/nonself discrimination by the immune system. Previous studies by ourselves and others have established two principles in immune regulation that have relevance here: the phenomenon of peripheral deletion, where responding T cells decrease in number during an immune response, and the phenomenon of immunological privilege, where responding T cells that enter some sites in the body undergo apoptosis rather than cause bystander damage to the tissue. Both of these depend in part on the presence of the Fas molecule (or related receptors) on T cells and its ligation by Fas- ligand (or related ligands) to trigger apoptosis. Here, we propose to unify these phenomena and explore the possibility that peripheral deletion occurs, at least in part, when the activated T cells induce peripheral tissues to express Fas-ligand (FasL), which in turn induces apoptosis in the activated T cells. In this way, peripheral tissues may have a mechanism, analogous to that of immunological privilege, whereby immunological damage to the tissues can be limited via inducible expression of FasL. While some tissues may have an extreme form of this, and thus always express FasL (such as the anterior chamber of the eye), other tissues may express FasL only when the immune response exceeds some threshold level that might go beyond """"""""acceptable"""""""" damage. Our preliminary studies provide some support for this novel idea. Therefore, we propose to answer the following questions. 1. What is the immunologic function of nonlymphoid FasL? Peripheral deletion of normal or TCR transgenic T cells in response to antigen will be followed in animals in which T cell vs. peripheral FasL is defective. 2. How do immune responses induce nonlymphoid FasL? We will examine the nature of the immune response that elicits FasL expression in nonlymphoid cells, in terms of T cell subsets, antigenic requirements, and the inducing signal. 3. What other death ligand/receptor pairs are expressed peripherally and contribute to peripheral deletion? In addition to Fas/FasL, other death ligand/receptor pairs are likely to also play roles in this phenomenon. Therefore we will examine some of these candidates for whether the relevant ligands are expressed on peripheral tissues, and if their interaction with T cells contributes to T cell apoptosis. Together, these studies will give us insights into the mechanisms whereby T cells induce expression of peripheral, nonlymphoid FasL and the roles this plays in immune homeostasis.
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