Role of nuclear orphan receptors during thymocyte differentiation

T细胞，一种白细胞，在生物体中巡逻以检测感染因子的存在。来自感染因子的抗原片段通过免疫系统的特化细胞与主要组织相容性复合体（MHC）的自身分子联合呈递给T细胞。T细胞通过其T细胞受体（TCR）识别外来物质（或抗原），诱导各种反应，从而消除病原体。因此，T细胞对对抗危及生命的微生物至关重要。***每个T细胞表达一种不同的TCR，能够识别一种特定的感染因子。这些不同的TCR是由基因组中编码TCR的不同基因片段随机并置产生的。这个过程可以产生多达10e15个不同的tcr。由于tcr是随机产生的，而且它们必须能够识别与自身分子相关的外来物质；需要测试T细胞表达的TCR的特异性，以确保：1)它不会对我们自己细胞表达的自身物质产生反应，以避免它们被破坏；2)它最终将能够识别与我们自身mhc分子相关的外来物质；3)它是在其产生的随机事件中正确产生的。这是在胸腺T细胞发育过程中进行的测试。更好地理解表达适当TCR的T细胞产生的机制对于理解T细胞如何成功消除外来物质而不产生自身免疫（自我攻击）至关重要。因此，我们建议的目标是更好地了解表达自反应性tcr的T细胞在胸腺发育过程中如何被消除。***所有发育过程和细胞对环境变化的反应都是由复杂的信号级联控制的。本资助申请中描述的工作将专门评估NR4A3分子的作用及其在胸腺T细胞发育过程中消除自身反应性T细胞的机制

T cells, a type of white blood cells, patrol the organism to detect the presence of infectious agent. Antigenic fragments coming from infectious agent are presented to T cells in association with self-molecules of the major histocompatibility complex (MHC), by specialized cells of the immune system. The recognition of foreign substances (or antigens) by T cells via their T cell receptor (TCR), induces a variety of responses that will permit the elimination of the pathogen. Thus, T cells are crucial to fight life-threatening microbes. ***Each T cell expresses a distinct TCR that will be able to recognize a particular infectious agent. These different TCRs are generated by random juxtaposition of the different gene segments coding for the TCR in the genome. This process can generate up to 10e15 different TCRs. Since TCRs are produced in a random fashion and since they will have to be able to recognize foreign substances in association with self-molecules; the specificity of the TCR expressed by a T cell needs to be tested to make sure that: 1) it is not reactive against self-substances expressed by our own cells to avoid their destruction; 2) it will eventually be able to recognize a foreign substances in association with our self-MHC molecules; and 3) it has been correctly produced during the random events of its generation. This is tested during T cell development in the thymus. A better understanding of the mechanism by which T cells expressing an appropriate TCR are generated is pivotal to understand how T cells successfully eliminate foreign substances without generating autoimmunity (self-attack). Thus the goal of our proposal is to better understand how T cells expressing self-reactive TCRs are eliminated during their development in the thymus.***All developmental processes and cellular responses to change in the environment are controlled by complex signaling cascades. The work described in this grant application will specifically evaluate the contribution of the molecule NR4A3 and the mechanism by which it contributes to the elimination of self-reactive T cells during thymic T cell development.**