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

描述（由申请人提供）：T细胞无反应性是外周耐受的一种重要机制，可控制自身免疫和同种异体免疫实验模型中免疫病理学的发展。无反应性涉及不适当的T细胞应答的功能失活，并且被认为主要是效应基因转录的主动沉默的结果。 也许受这种现象影响的最相关的基因编码T细胞生长因子IL-2，但在这种耐受性诱导模式中，该基因和其他基因被沉默的方式知之甚少。 我们发现，IL-2启动子包含两个假定的结合基序Ikaros，淋巴细胞特异性锌指DNA结合蛋白所需的正常T淋巴细胞的发展。有趣的是，Ikaros主要通过将组蛋白去乙酰化酶和染色质重塑复合物募集到基因启动子和增强子来作为转录抑制因子。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，因此可能有助于IL-2基因的主动沉默。 在这项资助申请中概述的拟议研究的具体目标是确定Ikaros是否调节IL-2基因在幼稚T细胞中的表达，以响应来自抗原和共刺激受体的信号，以及由该因子介导的染色质重塑是否有助于在诱导T细胞无能期间沉默IL-2基因。我们的假设，Ikaros和/或染色质重塑可能会影响IL-2基因的表达，诱导免疫耐受是新颖的，并代表了一种创新的方法来研究免疫耐受的分子基础。因此，拟议的研究与R21机制的探索性质一致。

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.