Receptor editing in development T cells

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DESCRIPTION (provided by the applicant): An important function of the thymus is to establish self-tolerance in developing T cells. The induction of apoptosis in developing clones that are specific for self-antigen is one mechanism that plays an important role. We recently described another mechanism for self-tolerance, namely receptor editing. Here self-reactive clones undergo gene rearrangement at the TCR alpha locus to produce a new receptor chain that alters the specificity of the clone. This application seeks to understand why clonal deletion occurs in some situations, but receptor editing in others. We will test two variables and determine if each plays a decisive role in the editing versus deletion decision. They are: tissue specificity of antigen presentation and timing of TCR expression during development. We also propose to determine the relative utilization of receptor editing and clonal deletion in the normal (non TCR transgenic) animals, by analysis of the V/J sequences present on excision circles. Finally, we will study the molecular mechanism of receptor editing, specifically testing the hypothesis that TCR ligation drives receptor editing not by inducing a signal for up-regulation of the recombination activating genes (RAG), but by preventing the signal for RAG repression. These issues are central to understanding the developmental biology of T cells. In addition, this topic has important implications for understanding immunologic self-tolerance because the health risks of receptor editing, namely the incidental generation of T cells with two receptor specificities, are quite distinct from those of clonal deletion.