Role of Ikaros in IL-2 gene expression and T cell anergy

Ikaros 在 IL-2 基因表达和 T 细胞无反应性中的作用

基本信息

批准号：
6874455
负责人：
ANDREW D WELLS
金额：
$ 25.5万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2006-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6874455
关键词：
T lymphocyte anergy chromatin chromatin immunoprecipitation enzyme linked immunosorbent assay gel mobility shift assay gene expression gene induction /repression genetically modified animals immune tolerance /unresponsiveness immunogenetics interleukin 2 laboratory mouse nuclear factor kappa beta protein structure function transcription factor

项目摘要

DESCRIPTION (provided by applicant): T cell anergy is an important mechanism of peripheral tolerance that controls the development of immunopathology in experimental models of autoimmunity and alloimmunity. Anergy involves the functional inactivation of inappropriate T cell responses and is thought to be largely the result of active silencing of effector gene transcription. Perhaps the most relevant gene affected by this phenomenon encodes the T cell growth factor IL-2, but the means by which this and other genes are silenced during this mode of tolerance induction is poorly understood. We find that the IL-2 promoter contains two putative binding motifs for Ikaros, a lymphoid-specific zinc-finger DNA binding protein required for normal T lymphocyte development. Interestingly, Ikaros acts primarily as a transcriptional repressor by recruiting histone deacetylases and chromatin remodeling complexes to gene promoters and enhancers. Our preliminary data suggest that Ikaros associates with the endogenous IL-2 promoter in primary T cells, and therefore could potentially contribute to active silencing of the IL-2 gene. The specific goal of the proposed studies outlined in this grant application is to determine whether Ikaros regulates IL-2 gene expression in naive T cells in response to signals from antigen and costimulatory receptors, and whether chromatin remodeling mediated by this factor contributes to silencing of the IL-2 gene during the induction of T cell anergy. Our hypothesis that Ikaros and/or chromatin remodeling may the influence IL-2 gene expression, and the induction of immune tolerance is novel, and represents an innovative approach to studying the molecular basis of immune tolerance. Therefore, the studies proposed are consistent with the exploratory nature of the R21 mechanism.

描述（由申请人提供）：T细胞消极是外周耐受性的重要机制，它可以控制自身免疫和同种免疫的实验模型中免疫病理学的发展。 Anergy涉及不适当的T细胞反应的功能失活，被认为主要是效应基因转录的主动沉默的结果。也许受到这种现象影响的最相关的基因编码T细胞生长因子IL-2，但是在这种耐受性诱导方式中，该基因和其他基因沉默的手段被鲜为人知。我们发现IL-2启动子包含两个假定的结合基序，Ikaros是正常T淋巴细胞发育所需的淋巴特异性锌指DNA结合蛋白。有趣的是，ikaros主要通过募集组蛋白脱乙酰基酶和染色质重塑络合物将基因启动子和增强子的染色质复合物起作用。我们的初步数据表明，Ikaros与原代T细胞中的内源性IL-2启动子相关联，因此有可能有助于IL-2基因的主动沉默。在本赠款应用中概述的拟议研究的具体目标是确定Ikaros对天真T细胞中的IL-2基因表达是否响应于抗原和costumulation受体信号的响应，以及该因子介导的染色质重塑是否有助于在T细胞诱导T细胞Anerergy诱导过程中IL-2基因沉默。我们的假设是Ikaros和/或染色质重塑可能会影响IL-2基因的表达，并且免疫耐受性的诱导是新颖的，并且代表了研究免疫耐受性的分子基础的创新方法。因此，提出的研究与R21机制的探索性质一致。