The induction of clonal expansion of T cells requires two biologically distinct signals. Signal 1 is generated by interaction of the T cell receptor (TCR) with a MHC-peptide complex, while signal 2 is generated by interaction of the costimulatory molecules on antigen-presenting cells with the receptors for such costimulators on the T cells. Recent studies using models involving CD4 T cells have demonstrated that the consequences of engaging T cell receptor with antigens are determined by delivery of the signal 2. Understanding the delivery of this signal is therefore critical to understanding the induction of the immune response and immune tolerance which has a broad range of significance on vaccination, autoimmunity and transplantation. Two molecules have recently been identified which can act as costimulatory molecules. B7 was originally identified by Linsley and coworkers as a costimulator which binds to CD28/CTLA4. We have recently identified the heat-stable antigen as another costimulator for T cells, although its receptor on T cells has not been identified. In this proposal, we will study the function and molecular basis of the costimulatory pathway mediated by the heat-stable antigen. Three kinds of information are being sought here. a. What is the role of the heat-stable antigen and B7 in CD8 T cell responses? b. What is the molecular basis of the costimulatory pathway mediated by the heat- stable antigen? c. What is the role of the heat stable protein in immune tolerance and autoimmunity? To achieve these goals, we need to study T cell responses to anti-CD3/TCR monoclonal antibodies as well as their specific antigens in a variety of in vivo and in vitro models. We need to use site-directed mutagenesis to generate different variants of the heat-stable antigen to study structural/functional relation of this costimulator molecule. We need to generate monoclonal antibodies which can bind to the putative receptor for the heat-stable antigen on the T cells and use it to clone the receptor on T cells. Finally, we need to use TCR transgenic mice and transgenic mice which express the heat-stable antigen on pancreatic beta cells.
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