VIRGIN AND MEMORY T CELLS IN SUPERANTIGEN INDUCED ANERGY

超抗原诱导的无能状态下的原始 T 细胞和记忆 T 细胞

• 批准号: 2442594
• 负责人: WILLIAM T LEE
• 金额: $ 9.62万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-15 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2442594
• 关键词: T lymphocyte; anergy; apoptosis; biological signal transduction; calcium flux; cytokine; flow cytometry; genetically modified animals; immunologic memory; laboratory mouse; leukocyte activation /transformation; protein kinase C; superantigens; tissue /cell culture

DESCRIPTION (Adapted from Investigator's abstract): In the periphery, an encounter with a foreign antigen stimulates lymphocyte activation and the generation of immunologic memory. Some cells that are in the periphery can recognize self-antigen and the development of immunologic memory must be prevented. The proposed study will attempt to elucidate the relationship between tolerance and memory development. This research application is based upon the described observation that memory T-cells are selectively tolerized to superantigens. In addition, the data suggest that there are differences between virgin and memory T-cells in their antigen recognition and signalling processes. The current study will characterize these differences using an animal model with which to study memory T-cell tolerance. T-cell receptor transgenic mice will be used to examine the processes underlying the responses to conventional antigens and superantigens, as the transgenic T-cell receptor recognized both peptide and superantigen. The specific aims of the study are 1) to determine the fate of cells subjected to superantigen-mediated tolerance. This would be approached by using flow cytometry to examine whether superantigens induce apoptosis or halt memory cells at a certain point in the cell cycle; 2) to discern differences in the signalling processes between virgin and memory T ells in response to a) conventional antigens and b) superantigens. This study will address signalling processes biochemically by looking at protein kinase C activation and intracellular calcium fluxes. Costimulatory signals that will induce or break tolerance in virgin and memory T-cells will also be examined. This will include the examination of possible co-factors such as stimulatory signals; 3) to determine the effect of tolerance on memory T-cell subset. These experiments will examine the roles of cytokines in maintaining or breaking tolerance and in modulating T-cell function. The studies will also determine whether normal TH1 and TH2 TM cell subsets are equally susceptible to superantigen-mediated tolerance. Previous studies have focussed on preventing disease onset by tolerizing potentially reactive virgin T-cells. One hypothesis that might be made from the aforementioned model would be that an ongoing autoimmune disease might be ameliorated by the induction of tolerance in autoimmune memory T-cells. The long-term goal of this research project will be to apply the results gained from the completion of these studies to therapies for autoimmune disease.

描述（根据调查员的摘要改编）： 外围，与外来抗原相遇刺激淋巴细胞 激活和免疫记忆的产生。一些细胞 在外围可以识别自我抗原和发展 必须防止免疫记忆。 拟议的研究将 试图阐明公差与记忆之间的关系 发展。该研究申请基于描述的 观察记忆T细胞有选择地耐受性 超抗原。 此外，数据表明有 抗原中处女与记忆T细胞之间的差异 识别和信号过程。当前的研究将 使用动物模型来表征这些差异 研究记忆T细胞公差。 T细胞受体转基因小鼠将 用于检查对响应的基础过程 常规抗原和超抗原作为转基因T细胞 受体识别肽和超抗原。具体目标 研究的1）确定受到细胞的命运 超抗原介导的耐受性。 通过使用 流式细胞仪检查超抗原是诱导凋亡还是 在细胞周期中的某个点停止记忆细胞； 2）辨别 处女和内存之间信号过程的差异 ELL响应A）常规抗原和B）超抗原。 这项研究将通过观察来解决生化的信号传导过程 在蛋白激酶C活化和细胞内钙通量上。 将在处女中诱导或破坏容忍度的共刺激信号和 内存T细胞也将进行检查。这将包括 检查可能的共同因素，例如刺激信号； 3） 确定公差对内存T细胞子集的影响。 这些实验将检查细胞因子在维持的作用 或破坏公差和调节T细胞函数。研究 还将确定正常的Th1和Th2 TM细胞子集是否为 同样容易受到超抗原介导的耐受性的影响。以前的 研究的重点是通过耐受性预防疾病发作 潜在的反应性维珍T细胞。 一个可能的假设 是由上述模型制成的 诱导耐受性可能会改善自身免疫性疾病 在自动免疫记忆中T细胞。 这项研究的长期目标 项目将在完成后应用结果 这些研究对自身免疫性疾病的疗法。