THE T-CELL RESPONSE TO ANTIGEN

T 细胞对抗原的反应

• 批准号: 6374616
• 负责人: HARVEY CANTOR
• 金额: $ 27.37万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6374616
• 关键词: T cell receptor; autoimmune disorder; autoimmunity; biological signal transduction; cellular immunity; cytotoxic T lymphocyte; gene expression; gene targeting; genetically modified animals; helper T lymphocyte; interferon gamma; interleukin 10; interleukin 12; laboratory mouse; leukocyte activation /transformation; macrophage; microbiology; natural killer cells; protein structure function; transcription factor; transposon /insertion element; virus infection mechanism

A gene product that may play an early and critical role in these responses is a T-cell cytokine we have cloned termed Eta-1 (for Early T-lymphocyte activation-1). This gene has the following features: the Eta-1 gene is the most abundant newly-transcribed mRNA species expressed after TCR ligation, encoding a secreted phosphoprotein that leads to macrophage activation and chemotactic migration in vitro and in vivo and may account for genetic resistance to several intracellular pathogens. Overexpression of Eta-1 may play a central role in the pathogenesis of autoimmune disease in MRL/lpr mice. Our recent studies indicate that mice deficient in Eta-1 gene expression secondary to targeted gene mutation fail to develop DTH responses and associated Th1-driven autoimmunity after viral infection. These defective immune responses are associated with diminished in vivo production of IL-12 and excessive production of IL-10. This in vivo response may reflect an interaction between the N- terminal portion of Eta-1 and its integrin receptor, alphavbeta3, leading to IL-12 secretion and inhibition of IL-10 expression. These findings identify Eta-1 as a critical and non-redundant cytokine that initiates Th1 inflammatory responses and provide a mechanism by which T-cell recognition of foreign antigens may govern the development of antimicrobial inflammatory responses. We propose structure/function studies to define the molecular interaction between Eta-1 and macrophage receptor(s) (SA1) and subsequent intracellular events (SA2) that regulate IL-12/IL-10 gene expression. We also propose studies to define the role of Eta-1 in Th1/DTH development to conventional antigen (SA3) and its contribution to Th1-dependent responses to microbiological pathogens and organ-specific autoimmune disease (SA4).

在这些反应中可能发挥早期和关键作用的基因产物是我们克隆的称为Eta-1（早期T淋巴细胞活化-1）的T细胞细胞因子。 该基因具有以下特征：Eta-1基因是TCR连接后表达的最丰富的新转录的mRNA种类，编码分泌的磷蛋白，其导致体外和体内巨噬细胞活化和趋化性迁移，并可能导致对几种细胞内病原体的遗传抗性。Eta-1的过表达可能在MRL/lpr小鼠自身免疫性疾病的发病机制中起重要作用。 我们最近的研究表明，Eta-1基因表达缺陷继发于靶基因突变的小鼠在病毒感染后不能发展DTH应答和相关的Th 1驱动的自身免疫。这些缺陷性免疫应答与IL-12的体内产生减少和IL-10的过量产生相关。这种体内反应可能反映了Eta-1的N-末端部分与其整联蛋白受体α v β 3之间的相互作用，导致IL-12分泌和IL-10表达的抑制。这些发现确定Eta-1作为一个关键的和非冗余的细胞因子，启动Th 1炎症反应，并提供了一种机制，通过这种机制，T细胞识别外源抗原可能会控制抗菌炎症反应的发展。我们提出了结构/功能研究，以确定Eta-1和巨噬细胞受体（SA 1）和随后的细胞内事件（SA 2），调节IL-12/IL-10基因表达的分子之间的相互作用。 我们还提出了研究，以确定Eta-1的作用，在Th 1/DTH的发展，以传统的抗原（SA 3）和其贡献的Th 1依赖性反应微生物病原体和器官特异性自身免疫性疾病（SA 4）。