CTLA-4 was first described as a negative regulatory molecule by our group in 1994. During the past 11years the molecule has been extensively studied. The molecule has been shown to have an intrinsic effecton T cell activation by directly delivering negative signals to T cells to shut down activation anddifferentiation. In addition, there have been a number of studies suggesting an extrinsic role for CTLA-4 asthe molecule has been proposed to be the effector molecule by which regulatory T cells suppress immunity.All of these 'functions' have been complicated by the recent discovery that CTLA-4 can be expressed as aB7 ligand non-binding variant that controls T cell activation. In addition, polymorphisms in the CTLA-4 genehas been linked to Graves Disease and Type 1 Diabetes. Thus, in this renewal, we will continue to addreessthe fundamental biology of CTLA-4. We propose to directly address both the intrinsic and extrinsic role ofCTLA-4 in the regulation of initial T cell activation, ongoing autoimmune responses and maintenance oftolerance. The following specific aims are proposed: 1. To study the biochemical basis of B7 ligand-dependentand ligand-independent CTLA-4-mediated inhibition of T cell function; 2. To study the intrinsicrole of CTLA-4 in T cell development, regulation of tolerance induction and development of diabetes in NODmice; and 3. To study the intrinsic role of CTLA-4 in T cell development, regulation of tolerance induction anddevelopment of diabetes in NOD mice. We will use a combination of novel mice and reagents, combinedwith TCR transgenic and bone marrow chimera models to identify the cellular and mechanistic basis forCTLA-4 regulation. The results of these studies will provide insights into the mechanisms of CTLA-4regulation of immunity, and test the the role of CTLA-4 in lymphoproliferative/homeostasis versus immuneactivation and tolerance are mediated by distinct extrinsic versus intrinsic pathways.Importantly, the information learned from this study may have important implications for public health forseveral reasons. T cells play a central role in immunity and autoimmunity. As such, any means to modulateT cell activity may lead to novel therapeutic approaches to treat these disease. Moreover, the fundamentalimportance of CTLA-4 in the induction and maintenance of peripheral tolerance is central to ourunderstanding of disease etiology and current therapeutic approaches.
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