REGULATION OF CD95 IN T CELLS IN A SERTOLI CELL LINE

描述(改编自调查者摘要)：最近它变成了 明确T淋巴细胞的程序性细胞死亡(也称为细胞凋亡) 与细胞的激活和增殖一样受到严格的调控。细胞 死亡是T细胞的一个重要事件，因为决定 胸腺细胞发育。此外，成熟的T细胞也会发生凋亡 在它们最初扩张以对抗一种刺激的抗原之后。它有 还表明，细胞凋亡是一种确保免疫豁免权的手段 在各种组织中。有趣的是，T的作用机制似乎 细胞在最初的免疫扩增后或在 渗透免疫特权部位，涉及CD95之间的相互作用 免疫特异体表面表达的T细胞和CD95配体 组织或T细胞本身。虽然许多研究都是 发表研究CD95信号转导机制的论文 调节T细胞凋亡，CD95配体如何作用尚不清楚 表达是受调控的。因此，这项提案的总体目标是 分析CD95配体在T细胞中的转录调控 细胞以及免疫特免权的模型系统中。要做到这一点 目标，提出了三个具体目标。第一个是调查 与基因表达和调控有因果关系的信号事件 CD95配体在基因转录水平。为此目的而进行的实验 涉及那些涉及MAP蛋白激酶家族哪些成员的问题 蛋白激酶在TCR诱导CD95配体表达中的重要作用 其他已知影响TCR介导的激活事件的分子是否也 对这种蛋白质的调节很重要。此外，在 为了达到这个目的，利用转基因小鼠构建了一种报告结构 包括CD95配体启动子的元件，被描述来研究 在体内对这种分子的调节。第二个具体目标是解决 活化T细胞核因子及其他转录因子的作用 T细胞CD95配体调节的因素。最终的具体目标 阐明哪些转录因子可能对调节 TM Sertoli细胞系中的CD95配体，一种免疫特权的模型 组织。总的来说，希望这些研究将提供洞察力。 CD95配体的表达调控，这可能有助于我们了解 调节这一重要分子的表达以达到潜在的治疗作用 目的。

DESCRIPTION (Adapted from Investigator's abstract): Recently it has become clear that programmed cell death (also known as apoptosis) of T lymphocytes is regulated as tightly as is cellular activation and proliferation. Cell death is an essential event for T cells as decisions are made about thymocyte development. Additionally, mature T cells undergo apoptosis following their initial expansion to combat an inciting antigen. It has been shown also that apoptosis occurs as a means to ensure immune privilege in various tissues. Interestingly it appears that the mechanism by which T cells undergo apoptosis, either following initial immune expansion or when infiltrating immune privileged sites, involves an interaction between CD95 on the surface of T cells and CD95 ligand expressed on immune privileged tissues or on T cells themselves. While numerous studies have been published investigating the mechanism by which CD95 signal transduction regulates T cell apoptosis, little is yet known about how CD95 ligand expression is regulated. The overall goal of this proposal, therefore, is to begin an analysis of the transcriptional regulation of CD95 ligand in T cells as well as in a model system for immune privilege. To achieve this goal, three specific aims are presented. The first is to investigate signaling events which are causally related to expression and regulation of CD95 ligand at the level of gene transcription. Experiments for this aim involve those addressing what members of the MAP kinase family of protein kinases are important for TCR induced expression of CD95 ligand and to ask whether other molecules known to impact TCR mediated activation events also are important for regulation of this protein. Additionally, experiments in this aim, making use of a mouse made transgenic for a reporter construct including elements of the CD95 ligand promoter, are described to investigate regulation of this molecule in vivo. The second specific aim addresses the role of nuclear factor of activated T cells as well as other transcription factors in CD95 ligand regulation in T cells. The final specific aim address what transcription factors may be important for the regulation of CD95 ligand in the TM Sertoli cell line, a model for an immune privileged tissue. Collectively, it is hoped that these studies will provide insight into the regulation of expression of CD95 ligand and may help us learn how to modulate expression of this important molecule for potential therapeutic purposes.