Regulation of IL-2 expression by the transcription factor Ets-1

描述（由申请人提供）：T辅助细胞分化成不同的亚群，负责控制免疫反应的结果。例如，Th1细胞指导针对病毒和细胞内细菌的免疫反应，而Th17细胞则需要根除某些细胞外细菌。然而，失调的辅助性T反应可引起免疫病理，如炎症性肠病或多发性硬化症。转录因子Ets-1在促进IL-2和IFN-？生产和Th1分化。同时，Ets-1主要通过促进IL-2抑制Th17分化。除了影响辅助性T细胞分化外，IL-2在免疫调节中起关键作用。虽然它是诱导T细胞记忆所必需的，但IL-2也维持调节性T细胞和外周耐受性。本研究的第一个目的是阐明Ets-1调控IL-2产生的分子机制。其次，Ets-1在Th1和Th17细胞中均有表达，尽管它抑制Th17细胞的分化。目前尚不清楚在T细胞中如何调节Ets-1的活性。在其他细胞类型中提出的激活和灭活磷酸化事件仅在T细胞中发挥非常温和的作用。因此，必须存在其他监管机制。Grenningloh博士最近发现了一种Ets-1突变体，它不能促进IL-2或IFN-？生产。本提案的第二部分旨在在分子水平上识别该突变体的缺陷。这将阐明T细胞中与其他细胞类型不同的Ets-1活性的调控。公共卫生相关性：辅助性T细胞指导免疫反应对抗感染因子，但也可引起自身免疫性疾病。这项研究的目的是了解调节T辅助细胞功能的转录因子Ets-1的功能，因此可能成为开发新治疗方法的有用靶点。

DESCRIPTION (provided by applicant): T helper cells differentiate into different subsets, which are responsible for controlling the outcome of an immune response. For example, Th1 cells direct the immune response against viruses and intracellular bacteria, while Th17 cells are required to eradicate certain extracellular bacteria. However, dysregulated T helper responses can cause immune pathology such as inflammatory bowel disease or multiple sclerosis. The transcription factor Ets-1 plays a major role in promoting IL-2 and IFN-? production and Th1 differentiation. At the same time, Ets-1 inhibits Th17 differentiation mainly through promoting IL-2. In addition to affecting T helper cell differentiation, IL-2 plays a pivotal role in immune regulation. While it is required for the induction of T cell memory, IL-2 also maintains regulatory T cells and therefore peripheral tolerance. The first aim of this proposal is directed at elucidating the molecular mechanisms by which Ets-1 regulates IL-2 production. Secondly, Ets-1 is expressed both in Th1 and Th17 cells, although it inhibits differentiation of the latter. It is unknown how Ets-1 activity is regulated in T cells. Activating and inactivating phosphorylation events that have been proposed in other cell types only play a very modest role in T cells. Therefore, other regulatory mechanisms must exist. Dr. Grenningloh has recently identified a mutant of Ets-1 that fails to promote IL-2 or IFN-? production. The second part of this proposal aims at identifying the defect of this mutant on a molecular level. This should shed light on the regulation of Ets-1 activity in T cells as opposed to other cell types. PUBLIC HEALTH RELEVANCE: T helper cells direct the immune response against infectious agents but can also cause autoimmune disease. The goal of this study is to understand the function of a transcription factor, Ets-1, that regulates T helper cell function and might therefore be a useful target for the development of new treatments.