This application is designed to study the factors which control the repertoire of alpha/beta T cell receptor (TCR) bearing T cells in mice. Contact with self antigen causes the death of immature T cell precursors. Contact with antigen can have several outcomes for mature T cells, however, including death, inactivation, or full blown response. The experiments in this application will investigate what determines which of these outcomes occurs. Variables to be studied will include receptor occupancy and the strength of the T cell response. Although positive selection, the fact that T cell precursors are selected to mature only if their receptors will be able to recognize antigenic peptides in association with self major histocompatibility complex (MHC) proteins has been known to occur for some years, the mechanisms whereby this phenomenon operates are not understood. It is thought that positive selection involves low affinity reactions between TCRs on developing T cells and MHC on thymus cortical epithelial cells. The experiments in this application will test this hypothesis and will also examine the idea that non-MHC, non-TCR background gene products help raise the avidity of the reaction between the developing T cells and its TCR and MHC on target thymus epithelial cells. One reason why progress in understanding of positive selection has been slow in that there is no easily manipulable experimental system for study of the problem. A cell line capable of inducing positive selection would, for example, be extremely useful. So far cell lines of this type have not been identified in in vitro tests, perhaps because no single cell line can provide all the factors needed for thymocyte growth and maturation. Experiments described in this application will test thymus epithelial cell lines for their ability to participate in positive selection in whole thymuses. Many autoimmune diseases are driven by autoimmune T cells, cells which have somehow inadvertently broken through the processes of self tolerance induction. The studies in this application are designed to test why this might occur, and what can be done about it.
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