Regulation of T cell differentiation by the nuclear orphan receptor NR4A3

核孤儿受体 NR4A3 对 T 细胞分化的调节

• 批准号: RGPIN-2014-03599
• 负责人: Labrecque, Nathalie
• 金额: $ 2.99万
• 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: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=565969
• 关键词: Regulation; cell; differentiation; nuclear; orphan

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.

T 细胞是白细胞的一种，在生物体中巡逻以检测传染源的存在。来自感染原的抗原片段由免疫系统的专门细胞与主要组织相容性复合体 (MHC) 的自身分子结合呈递给 T 细胞。 T 细胞通过 T 细胞受体 (TCR) 识别外来物质（或抗原），诱导多种反应，从而消除病原体。因此，T 细胞对于对抗危及生命的微生物至关重要。每个 T 细胞都表达独特的 TCR，能够识别特定的感染因子。这些不同的 TCR 是通过基因组中编码 TCR 的不同基因片段随机并置而产生的。这个过程可以生成多达 10e15 个不同的 TCR。由于 TCR 是以随机方式产生的，并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）它不会与我们自身细胞表达的自身物质发生反应，以避免其被破坏； 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）它是在其生成的随机事件期间正确生成的。这是在胸腺 T 细胞发育过程中进行测试的。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身反应性 TCR 的 T 细胞在胸腺中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由复杂的信号级联控制。本拨款申请中描述的工作将具体评估特定分子 NRA3 的贡献及其在胸腺 T 细胞发育过程中消除自身反应性 T 细胞的机制。