Effector cell gene regulation by Egr factors

描述(由申请人提供)： 从原始的CD4+T细胞分化为具有不同细胞因子表达谱的Th1和Th2效应亚群是建立对抗原攻击的适当和有效反应的关键。虽然Th1和Th2细胞发育的模式已被广泛认可，但推动这一过程的分子机制尚不完全清楚。除了每个亚群产生的标志性细胞因子外，Fas配体(CD95L，FasL)的表达仅限于THL细胞，因此是开始研究CD4+T细胞表型发育基础的合适课题。已经证明，核因子-AT和早期生长反应(Egr)家族的成员对于最大限度地激活诱导FasL的表达是重要的，尽管每个成员对最佳表达的贡献尚不清楚。也有研究表明，表达FasL的Th1细胞缺乏Egr-3的表达，而在FasL缺陷的Th2细胞中很容易检测到Egr-3的表达。需要检验的假设是，Egr和NF-AT家族成员直接作用于FasL启动子是实现最佳表达所必需的，而Egr-3可以作为竞争调节因子，抑制FasL的表达。一个更广泛的假设是，在FasL转录调控模型中，Egr-3在Th1和Th2细胞中的差异表达，假设Egr因子在效应性T细胞亚群的产生中发挥关键作用。具体目的将集中在证明Egr和NF-AT家族成员直接作用于FasL启动子是获得最佳FasL表达所必需的协同作用，Egr-3具有Egr-3对FasL表达的负调控特性，以及Egr因子参与Th1和Th2亚群的发育。

DESCRIPTION (provided by applicant): The differentiation from naive CD4+ T cells into Thl and Th2 effector subsets having distinct cytokine expression profiles is crucial to mounting an appropriate and effective response to antigenic challenge. While the paradigm of Thl and Th2 cell development is widely acknowledged, the molecular mechanisms driving this process are incompletely understood. In addition to the signature cytokines that each subset produce, the expression of Fas ligand (CD95L, FasL) has been demonstrated to be limited to Thl cells and therefore is an appropriate subject to begin to study the basis of CD4+ T cell phenotype development. It has been demonstrated that members of the NF-AT and early growth response (Egr) families are important for maximal activation-induced expression of FasL, though in what capacity each member contributes to optimal expression is unknown. It has also been shown that FasL-expressing Thl cells lack expression of Egr-3 whereas Egr-3 expression is easily detected in FasL-deficient Th2 cells. The hypothesis to be tested is that a cooperative interaction of Egr and NF-AT family members acting directly at the FasL promoter is required for optimal expression and that Egr-3 can function as a competitive regulator, suppressing FasL expression. A broader hypothesis, founded on the differential expression of Egr-3 in Thl and Th2 cells in the FasL transcriptional regulation model, posits that Egr factors play a pivotal role in the generation of effector T cell subsets. The specific aims will focus on demonstrating that a cooperative interaction of Egr and NF-AT family members acting directly at the FasL promoter is required for optimal FasL expression, that Egr-3 has negative regulatory properties of Egr-3 with respect to FasL expression, and that Egr factors are involved in Thl and Th2 subset development.