Regulation of IL-2 Gene Expression in T-cell Anergy

描述（由申请人提供）：正常的免疫系统需要 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反应的发展。 克隆无反应性已被提出作为这种控制的一种潜在机制。 辅助性T细胞的免疫反应性。它被定义为T细胞的一种状态， 无反应性，防止其对抗原的反应性增殖 刺激.先前的研究表明，IL-2的产生缺陷 是这种反应迟钝的基础，这是由于信号的阻塞， 转导至IL-2基因增强子。从原子核往回看， 现已证明：a）IL-2增强子处的反式激活失败，B）AP-1 核复合体形成缺陷，c）c-fos、fosB和junB表达 d）ERK、JNK和p38激活被阻断，尽管 正常的蛋白质水平。因此，MAPK上游信号转导的缺陷 TCR/CD 3复合物和p21 ras之间偶联水平的活化 似乎是克隆性无能的原因也许与此相一致， 异核体分析表明，存在显性作用 抑制剂分子。最后，我们的工作揭示了 对于TCR和CD 28信号在Elk-I转录水平上的整合 因子，这可能被证明是一个额外的网站的调节克隆 c-fos基因无反应性。有了这些新的信息，这个研究项目将 再次靶向TCRJp 2 1 ras/MAPK/AP-I/IL-2基因信号转导 进一步研究的途径，并确定这些生化改变 从而损害IL-2基因的表达。具体而言，这项研究将： a）确定TCR的生物化学、分子遗传和功能性质 正常人中Elk-1/CBP反式激活水平的CD 28信号整合 和无反应性Th 1细胞，和B）探索IL-2基因阻遏的性质， 克隆无能使用异核体分析。在此过程中获得的信息 这项研究将更好地了解生物化学机制， 被免疫系统用来调节对外来和 自身抗原，并可能证明是必不可少的设计有效的临床 治疗感染、癌症和自身免疫性疾病。

DESCRIPTION (provided by applicant): The normal immune system requires 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. It is defined as a state of T-cell unresponsiveness that prevents their proliferation in response to antigen stimulation. Previous research has suggested that defective IL-2 production underlies this unresponsiveness, and this arises from of a block in signal transduction to the IL-2 gene enhancer. Working back from the nucleus, it has now been shown that: a) trans-activation at the IL-2 enhancer fails, b) AP-1 nuclear complex formation is defective, c) c-fos, fosB and junB expression cannot be induced and d) ERK, JNK and p38 activation are blocked, despite normal protein levels. Thus, a defect in signal transduction up-stream of MAPK activation at the level of coupling between the TCR/CD3 complex and p21 ras appears to be the cause of clonal anergy. Perhaps consistent with this, a heterokaryon analysis has demonstrated the presence of a dominant-acting repressor molecule in anergic T cells. Finally, our work has revealed a role for TCR and CD28 signal integration at the level of the Elk-I transcription factor, and this may prove to be an additional site of regulation by clonal anergy at the c-fos gene. With this new information, this research project will once again target the TCRJp2 1 ras/MAPK/AP- I /IL-2 gene signal transduction pathway for further investigation, and define those biochemical alterations that impair the expression of the IL-2 gene. Specifically, this research will: a) Determine the biochemical, molecular genetic and functional nature of TCR and CD28 signal integration at the level Elk-1/CBP trans-activation in normal and anergic Thl cells and b) Explore the nature of IL-2 gene repression in clonal anergy using a heterokaryon analysis. The information gained in this study will provide a better understanding of the biochemical mechanisms utilized by the immune system to regulate responsiveness to foreign and self-antigens, and may prove essential to the design of effective clinical therapies for infection, cancer and autoimmune diseases.