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

描述(申请人提供)：T细胞无能是外周免疫耐受的重要机制，在自身免疫和同种异体免疫的实验模型中控制免疫病理学的发展。无能涉及不适当T细胞反应的功能失活，被认为在很大程度上是主动沉默效应基因转录的结果。也许受这一现象影响最相关的基因编码T细胞生长因子IL-2，但在这种耐受诱导模式中，该基因和其他基因沉默的方式尚不清楚。 我们发现IL-2启动子包含两个假定的与Ikaros结合的基序，Ikaros是一种淋巴特异性的锌指DNA结合蛋白，是正常T淋巴细胞发育所必需的。有趣的是，Ikaros主要作为转录抑制因子，招募组蛋白去乙酰酶和染色质重塑复合体为基因启动子和增强子。我们的初步数据表明，Ikaros与原代T细胞内源性IL-2启动子相关，因此可能有助于主动沉默IL-2基因。 在这项拨款申请中概述的拟议研究的具体目标是确定Ikaros是否调节幼稚T细胞中IL-2基因的表达以响应来自抗原和共刺激受体的信号，以及该因子介导的染色质重塑是否有助于在T细胞无能诱导过程中沉默IL-2基因。我们的假设是Ikaros和/或染色质重塑可能影响IL-2基因的表达，并且免疫耐受的诱导是新颖的，代表了研究免疫耐受的分子基础的一种创新方法。因此，所提出的研究与R21机制的探索性是一致的。

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.