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

描述(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 可抑制病原体，防止病理性自身免疫反应的发展。 克隆无能已被认为是这种控制的一种潜在机制。 辅助性T细胞的免疫反应性。它定义为T细胞的一种状态 无反应性，阻止它们对抗原的反应而增殖 刺激。先前的研究表明，有缺陷的IL-2产生 这是这种无反应的基础，而这是由信号中的阻塞引起的 转导至IL-2基因增强子。从原子核向后工作，它有 现在已经证明：a)IL-2增强子的反式激活失败，b)AP-1 C)c)c-fos、FosB和JunB的表达 不能被诱导，d)ERK、JNK和p38的激活被阻断，尽管 蛋白质水平正常。因此，MAPK上游的信号转导存在缺陷 TCR/CD3复合体与p21ras偶联水平的激活 似乎是克隆性无能的原因。也许与此相一致，一个 异核体分析已经证明了显性作用的存在 无能T细胞中的抑制分子。最后，我们的工作揭示了一个角色 在ELK-I转录水平上进行TCR和CD28信号整合 因子，这可能被证明是克隆调控的一个额外部位。 C-fos基因无能。有了这些新的信息，这项研究项目将 再次靶向TCRJp21/MAPK/AP-I/IL-2基因信号转导 进一步研究的途径，并定义这些生化变化 这会损害IL-2基因的表达。具体来说，这项研究将： A)确定TCR的生化、分子遗传和功能性质 和CD28信号整合在ELK-1/CBP反式激活水平上 和无能Thl细胞，以及b)探讨IL-2基因抑制的本质。 用异核体分析克隆无能。从这一过程中获得的信息 研究将提供对生化机制的更好的理解 被免疫系统用来调节对外来和 自身抗原，并可能被证明是有效的临床设计所必需的 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.