Regulation of T cell differentiation by the nuclear orphan receptor NR4A3

T细胞是一种白细胞，它在生物体内巡逻，以检测是否存在感染性物质。来自感染剂的抗原片段由免疫系统中的特殊细胞与主要组织相容性复合体(MHC)的自身分子一起呈递给T细胞。T细胞通过其T细胞受体(TCR)识别外来物质(或抗原)，引起各种反应，从而消除病原体。因此，T细胞对于对抗威胁生命的微生物至关重要。每个T细胞表达一种独特的TCR，能够识别特定的感染源。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而产生的。此过程最多可生成10E15个不同的TCR。由于TCR是以随机方式产生的，而且它们必须能够识别与自身分子相关的外来物质；T细胞表达的TCR的特异性需要进行测试，以确保：1)它不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；以及3)它是在其生成的随机事件中正确产生的。这是在胸腺中T细胞发育过程中进行的测试。更好地了解表达适当TCR的T细胞的产生机制，对于理解T细胞如何在不产生自身免疫(自我攻击)的情况下成功清除异物至关重要。因此，我们建议的目标是更好地了解表达自身反应性TCR的T细胞在胸腺发育过程中是如何被消除的。所有发育过程和细胞对环境变化的反应都受复杂的信号级联反应控制。在这项拨款申请中描述的工作将专门评估特定分子NRA3的贡献，以及它在胸腺T细胞发育过程中帮助消除自身反应性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 fragment 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), induced a variety of responses that will permit the elimination of the pathogen. Thus, T cells are crucial to fight life-threatening microbes. Each T cells 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 expresses 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 specific molecule NRA3 and the mechanism by which it contributes to the elimination of self-reactive T cells during thymic T cell development.