Receptor editing in development T cells

描述(由申请人提供)：胸腺的一个重要功能是在发育中的T细胞中建立自我耐受。在发育中的针对自身抗原的克隆中，诱导细胞凋亡是发挥重要作用的机制之一。我们最近描述了另一种自我耐受的机制，即受体编辑。在这里，自我反应性克隆在TCRα基因上进行基因重排，以产生新的受体链，从而改变克隆的特异性。这个应用程序试图理解为什么在某些情况下会发生克隆删除，但在其他情况下会发生受体编辑。我们将测试两个变量，并确定每个变量是否在编辑与删除决策中起决定性作用。它们是：抗原提呈的组织特异性和发育过程中TCR表达的时机。我们还建议通过分析切除环上存在的V/J序列来确定正常(非TCR转基因)动物中受体编辑和克隆删除的相对利用率。最后，我们将研究受体编辑的分子机制，特别是验证这样的假设，即TCR连接驱动受体编辑不是通过诱导重组激活基因(RAG)上调的信号，而是通过阻止RAG抑制的信号。这些问题是理解T细胞发育生物学的核心。此外，这一主题对于理解免疫自我耐受具有重要意义，因为受体编辑的健康风险，即偶然产生具有两种受体特异性的T细胞，与克隆缺失的T细胞完全不同。

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.