Role of nuclear orphan receptors during thymocyte differentiation

核孤儿受体在胸腺细胞分化过程中的作用

• 批准号: RGPIN-2015-06645
• 负责人: Labrecque, Nathalie
• 金额: $ 2.77万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=687212
• 关键词: Role; nuclear; orphan; receptors; during

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.**

T细胞是一种白色血细胞，它在机体内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）的自身分子一起呈递给T细胞。T细胞通过它们的T细胞受体（TCR）识别外来物质（或抗原），诱导将允许病原体消除的多种应答。因此，T细胞对于对抗威胁生命的微生物至关重要。* 每个T细胞表达能够识别特定感染因子的不同TCR。这些不同的TCR是通过基因组中编码TCR的不同基因区段的随机并置产生的。这个过程可以产生多达10 e15个不同的TCR。由于TCR是以随机方式产生的，并且由于它们必须能够识别与自身分子相关的外来物质，因此需要测试T细胞表达的TCR的特异性以确保：1）它不与我们自己的细胞表达的自身物质反应以避免它们的破坏; 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）它在其生成的随机事件期间被正确地产生。这在胸腺中的T细胞发育期间进行测试。更好地理解产生表达适当TCR的T细胞的机制对于理解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身反应性TCR的T细胞在胸腺发育过程中如何被消除。所有的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。这项资助申请中描述的工作将专门评估分子NR 4A 3的贡献及其在胸腺T细胞发育过程中有助于消除自身反应性T细胞的机制。