REGULATION OF IL-2 GENE EXPRESSION IN T CELL ANERGY

描述(改编自调查者摘要)正常免疫系统 具有调节T细胞功能的能力，以抵抗 还能防止病理性自身免疫的发展 回应。克隆无能已经被认为是一种潜在的机制 这种对辅助T细胞免疫反应性的控制。无能的定义是 阻止T细胞增殖的T细胞无反应状态 对抗原刺激的反应。先前的研究表明，有缺陷的 IL-2的产生是这种无反应的基础，而这是由于 阻断IL-2基因增强子的信号转导。具体地说，它 已经表明：a)AP-1站点的激活失败，b)AP-1 C)c)c-fos、FosB和JunB的表达 无法诱导，d)ERK和JNK激活被阻止，尽管正常 蛋白质水平，和e)PMA激活PKC绕过克隆性无能 叛逃。因此，MAPK激活的上游信号转导存在缺陷 在TCR/CD3复合体和p21ras之间的偶联水平上似乎 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/p21ras/MAPK/AP-1信号转导通路 进一步的研究，并定义那些损害 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.