REGULATION OF IL-2 GENE EXPRESSION IN T CELL ANERGY

描述（改编自研究者摘要）正常免疫系统 具有调节T细胞功能的能力，以抵抗 病原体，但防止病理性自身免疫性疾病的发展， 应答 克隆无反应性已被提出作为一种潜在的机制， 这种对辅助性T细胞免疫反应的控制。 无反应性被定义为 一种T细胞无反应状态，阻止它们在 对抗原刺激的反应。 先前的研究表明， IL-2的产生是这种无反应性的基础，这是由于 阻断IL-2基因增强子的信号转导。 具体 已经表明：a）AP-1位点的反式激活失败，B）AP-1 核复合体形成缺陷，c）c-fos、fosB和junB表达 d）ERK和JNK激活被阻断，尽管正常 蛋白水平，和e）PKC的PMA活化绕过克隆无反应性 缺损 因此，MAPK激活上游信号转导的缺陷 在TCR/CD 3复合物和p21 ras之间的偶联水平， 是克隆性无能的原因 有了这些新的信息，这项研究 该项目将针对TCR/p21 ras/MAPK/AP-1信号转导通路， 进一步的调查，并确定这些生化改变，损害 IL-2基因的表达。

DESCRIPTION (Adapted from Investigator's abstract) The normal immune system has the capacity to regulate T-cell function, in order to resist the effects of pathogens and yet prevent the development of pathological autoimmune responses. Clonal anergy has been proposed as one potential mechanism for this control of immune reactivity in helper T cells. Anergy is defined as a state of T-cell unresponsiveness that prevents their proliferation in response to antigen stimulation. Previous studies indicated that defective IL-2 production underlies this unresponsiveness, and this arises from a block in signal transduction to the IL-2 gene enhancer. Specifically, it has been shown that: a) transactivation at AP-1 sites fails, b) AP-1 nuclear complex formation is defective, c) c-fos, fosB, and junB expression cannot be induced, d) ERK and JNK activation are blocked, despite normal protein levels, and e) PMA activation of PKC bypasses the clonal anergy defect. Thus, a defect in signal transduction up-stream of MAPK activation at the level of coupling between the TCR/CD3 complex and p21ras appears to be the cause of clonal anergy. With this new information, this research project will target the TCR/p21ras/MAPK/AP-1 signal transduction pathway for further investigation, and define those biochemical alterations that impair the expression of the IL-2 gene.