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

描述(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细胞直接针对病毒和细胞内细菌进行免疫反应，而Th17细胞需要清除某些细胞外细菌。然而，调节失调的T辅助反应可导致免疫病理，如炎症性肠病或多发性硬化症。转录因子Ets-1在促进IL-2和干扰素？产生和Th1分化。同时，ETS-1主要通过促进IL-2抑制Th17分化。IL-2除了影响辅助性T细胞的分化外，还在免疫调节中起着关键作用。虽然IL-2是诱导T细胞记忆所必需的，但它也维持调节性T细胞，从而维持外周耐受。这项建议的第一个目的是阐明ETS-1调节IL-2产生的分子机制。其次，ETS-1在Th1和Th17细胞中都有表达，但它抑制Th17细胞的分化。目前尚不清楚T细胞中ETS-1的活性是如何调节的。在其他类型的细胞中已经提出的激活和失活磷酸化事件在T细胞中只起到非常小的作用。因此，必须存在其他监管机制。Grenningloh博士最近发现了ETS-1的一个突变体，该突变体无法促进IL-2或干扰素？制作。这项建议的第二部分旨在从分子水平上鉴定该突变体的缺陷。这应该有助于阐明T细胞中ETS-1活性的调节，而不是其他细胞类型。与公共卫生相关：T辅助细胞可引导对感染性病原体的免疫反应，但也可导致自身免疫性疾病。这项研究的目的是了解转录因子Ets-1的功能，该转录因子调节T辅助细胞功能，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.