THE T-CELL RESPONSE TO ANTIGEN

T 细胞对抗原的反应

• 批准号: 6511531
• 负责人: HARVEY CANTOR
• 金额: $ 28.12万
• 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/6511531
• 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).

可能在这些反应中起早期和关键作用的基因产物是T细胞细胞因子，我们被克隆为称为ETA-1（对于早期的T淋巴细胞激活1）。 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物种，编码一种分泌的磷蛋白，可导致体外和体内巨噬细胞激活和趋化性迁移，并可能占多种细胞内细胞病原病原体的遗传性。 ETA-1的过表达可能在MRL/LPR小鼠自身免疫性疾病的发病机理中起核心作用。 我们最近的研究表明，缺乏靶向基因突变继发于ETA-1基因表达的小鼠无法发展DTH反应，并且在病毒感染后与TH1驱动的自身免疫相关。这些有缺陷的免疫反应与IL-12的体内产生和IL-10产生过多有关。这种体内反应可能反映了ETA-1的N末端部分与其整合素受体Alphavbeta3之间的相互作用，从而导致IL-12分泌和抑制IL-10表达。这些发现将ETA-1鉴定为启动Th1炎症反应的关键和非冗余细胞因子，并提供了一种机制，通过这种机制，T细胞对外国抗原的识别可能控制抗菌炎症反应的发展。我们提出了结构/功能研究，以定义ETA-1与巨噬细胞受体（S）（SA1）以及随后调节IL-12/IL-10基因表达的细胞内事件（SA2）之间的分子相互作用。 我们还提出了研究，以定义ETA-1在TH1/DTH发育中对常规抗原（SA3）的作用及其对TH1依赖性反应对微生物病原体和器官特异性自身免疫性疾病的贡献（SA4）。