Effector cell gene regulation by Egr factors

描述（由申请人提供）： 从初始CD 4 + T细胞分化成具有不同细胞因子表达谱的Thl和Th 2效应子亚群对于对抗原攻击产生适当和有效的应答是至关重要的。虽然Thl和Th 2细胞发育的范例被广泛认可，但驱动该过程的分子机制尚未完全理解。除了每个亚群产生的标志性细胞因子外，Fas配体（CD 95 L，FasL）的表达已被证明限于Thl细胞，因此是开始研究CD 4 + T细胞表型发育基础的合适对象。已经证明NF-AT和早期生长反应（Egr）家族的成员对于FasL的最大活化诱导表达是重要的，尽管每个成员以何种能力促进最佳表达是未知的。还显示表达FasL的Thl细胞缺乏Egr-3的表达，而Egr-3表达在FasL缺陷型Th 2细胞中容易检测到。待检验的假设是，Egr和NF-AT家族成员直接作用于FasL启动子的协同相互作用是最佳表达所需的，并且Egr-3可以作为竞争性调节剂发挥作用，抑制FasL表达。一个更广泛的假设，建立在FasL转录调控模型中的Th 1和Th 2细胞中Egr-3的差异表达，假定Egr因子在效应T细胞亚群的产生中起关键作用。具体的目标将集中在证明Egr和NF-AT家族成员直接作用于FasL启动子的合作相互作用是最佳FasL表达所需的，Egr-3具有Egr-3对FasL表达的负调控特性，并且Egr因子参与Th 1和Th 2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.