T CELL RESPONSES TO LOW AFFINITY LIGANDS FOR THE TCR

T 细胞对 TCR 低亲和力配体的反应

• 批准号: 6254671
• 负责人: GILBERT J. KERSH
• 金额: $ 25.41万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-15 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6254671
• 关键词: T cell receptor; T lymphocyte; autoimmunity; enzyme activity; gene expression; genetic promoter element; genetically modified animals; laboratory mouse; leukocyte activation /transformation; ligands; mitogen activated protein kinase; transcription factor

DESCRIPTION (Applicant's Abstract): The T-cell receptor (TCR) recognizes not only cognate ligands consisting of an antigenic peptide complexed with MHC molecules, but also low affinity ligands formed by self peptide/MHC complexes. Recognition of low affinity ligands by the TCR is required for: a) positive selection of thymocytes, which produce a repertoire of T-cells bearing useful TCR specificities, and b) maintenance and survival of peripheral T-cells. However, little is known about how these low affinity TCR-ligand interactions induce molecular changes within the cell that result in these biologically important responses. The goal of this study is to understand how recognition of low affinity ligands can induce gene transcription important for these responses. The zinc-finger transcriptional activator early growth response gene 1 (Egr-1) has been implicated in the response to low affinity TCR ligands by virtue of its expression in T-cells and thymocytes in response to TCR ligation, and by a change in the threshold for positive selection in mice that over-express Egr-1. Furthermore, in non-lymphoid cell types, Egr-l is known to play a role in inducing differentiation in response to extracellular stimuli. The co-repressor Nab-2 regulates the transcriptional activation mediated by Egr- 1. This evidence leads to the hypothesis that Egr- 1 and Nab-2 are two genes that are regulated by TCR interaction with low affinity ligands, resulting in a temporal window in which new gene transcription is activated that leads to positive selection and T-cell survival. Using a TCR transgenic system that has numerous ligands covering a range of TCR affinities, we will define the regulation of Egr-1 and Nab-2 by high and low affinity TCR ligands. This will include analysis of the factors that bind to the Egr-l and Nab-2 promoters, and the signaling pathways that regulate these factors. In addition, the specific roles that Egr- 1 and Nab-2 play in positive and negative selection, T-cell homeostasis, and peripheral T-cell differentiation will be defined using mice that contain targeted deletions in the genes for Egr-l or Nab-2. The results of these experiments will contribute significantly to a molecular understanding of T-cell responses to low affinity ligands.

描述（申请人的摘要）：T细胞受体（TCR）不识别 仅由与MHC复合的抗原肽组成的同源配体 分子，也是由自肽/MHC复合物形成的低亲和力配体。 需要以下TCR识别低亲和力配体：a）阳性 胸腺细胞的选择，产生有用的T细胞曲目 TCR特异性以及b）周围T细胞的维持和存活。 但是，对于这些低亲和力TCR - 配体相互作用如何了解 在细胞内诱导分子变化，从而导致这些生物学 重要的回应。这项研究的目的是了解如何认识 低亲和力配体可以诱导基因转录对这些转录很重要 回答。锌指转录激活剂早期生长反应基因 1（Egr-1）与对低亲和力TCR配体的响应有关 响应TCR连接的T细胞和胸腺细胞中表达的优点， 并且通过改变小鼠阳性选择阈值的改变 过表达EGR-1。此外，在非淋巴细胞类型中，已知EGR-L已知 在诱导细胞外刺激的诱导分化中发挥作用。 共抑制器NAB-2调节由 Egr-1。该证据导致了以下假设：Egr-1和Nab-2是两个 由TCR相互作用与低亲和力配体相互作用的基因， 导致一个新基因转录激活的时间窗口 这导致阳性选择和T细胞存活。使用TCR转基因 系统具有许多涵盖一系列TCR亲和力的系统，我们将 通过高和低亲和力TCR配体定义EGR-1和NAB-2的调节。 这将包括分析与EGR-L和NAB-2结合的因素 启动子以及调节这些因素的信号通路。此外， EGR-1和NAB-2在正面和负面发挥的特定作用 选择，T细胞稳态和周围T细胞分化将是 使用在Egr-l或 NAB-2。这些实验的结果将对 对低亲和力配体T细胞反应的分子理解。