It has become increasingly evident that clonal deletion in the thymus cannot entirely account for the normal absence of T cell responses to self antigen. Instead, mechanisms by which T cells are deleted or rendered non-responsive must operate in mature T cells in the periphery. This program will address the nature of these mechanisms at the molecular and cellular levels using both in vitro and in vivo models. Project 1 will characterize the requirements for in vivo induction of anergy in TH1 cells. Project II will examine lymphokine production by THO cells following induction of anergy to test the hypothesis that an anergic stimulus converts THO cells to a TH2 functional phenotype. Mechanisms which might render mature CD8+ cytolytic T lymphocytes non-responsive have been less well studied than those for CD4 cells. Project IV will examine two potentially important mechanisms for which some evidence exists; the induction of cell death by apoptosis as a result of a 'strong' antigen stimulus, and the antigen-dependent induction of an anergic state resembling that found for CD4+ cells. A major impetus for developing a better understanding of peripheral T cell tolerance is the potential benefit to be derived from an ability to manipulate the tolerance state in transplantation. Project III employs a murine model for GVH disease to develop methods for manipulating the disease state based on the developing understanding of the mechanisms involved. Thus, this program brings together five investigators with diverse range of perspectives on the issues of peripheral tolerance, each having established model systems for further elucidating critical questions.
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