The objective of this project is to analyze the mechanisms that determine the choice between peripheral T cell tolerance and autoimmune disease against model systemic and tissue-restricted self antigens. We will exploit a panel of antigen receptor transgenic mice carrying mutations in tolerance pathways (Fas, CTLA-4), and mice expressing the cognate antigens in tissues (pancreatic islet beta cells) and in the circulation, to address the following specific aims. 1. The hypothesis underlying this aim is that different mechanisms of peripheral tolerance, such as Fas-mediated deletion and CTLA4-mediated anergy, may be responsible for maintaining tolerance to different types of self antigens, and preventing different manifestations of autoimmunity. We will define the roles of T cell deletion and anergy in maintaining tolerance to tissue and systemic antigens, using T cell transfers into antigen-expressing recipients. We will examine the survival and functional responsiveness of normal T cells and cells with mutations in Fas/FasL or CTLA-4, to define the consequences of self antigen encounter and the failure of these mechanisms of tolerance. 2. Cytokine dysregulation in autoimmunity. In this aim we will examine the roles of two cytokines, IL-2 and TGF-beta in tolerance to self antigens. We will examine the interactions of TCR transgenic T cells lacking IL-2 or IL-2R, or expressing a dominant negative form of the TGF-beta receptor, with cognate antigens in vivo. We will define the patterns of autoimmune reactions, and the defects in T cells that correlate with the development of autoimmunity . 3. Mechanisms of tolerance induction in vivo. In this aim, we will analyze the biochemical mechanisms of tolerance, initially by isolating T cells that have encountered self antigens in vivo and defining their patterns of gene expression. We will also express selected genes in T cells that trigger specific biochemical pathways, and determine if expression of these genes interferes with tolerance induction. 4. Role of infections in autoimmunity. To examine the effects of infections in triggering autoimmune reactions, and ask if microbes may do this by inducing costimulators or by molecular mimicry, we will express defined protein antigens in a prototype virus (Coxsackie), and determine if and how the virus with and without the antigen breaks tolerance to that antigen expressed in tissues. Thus, this project will address fundamental questions about the control of T cell tolerance in vivo and the mechanisms that may lead to systemic and tissue autoimmune diseases.
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