Regulation of Foxp3 Function

描述（由申请人提供）：调节性T细胞在器官移植排斥反应和自身免疫性疾病中对免疫介导的病理控制至关重要，因此了解这些细胞功能的潜在机制对于促进人类免疫耐受至关重要。最近的实验模型研究表明，Foxp3是DNA结合蛋白叉头家族的一员，对于调节性T淋巴细胞谱系选择和功能的规范是必要和充分的。因此对获得性免疫耐受至关重要。Foxp3的表达启动了一个独特的转录程序，包括诱导基因如GITR、CD25、CTLA-4、IL-10和TGF2，以及抑制促炎细胞因子基因如IL-2和IFN？Foxp3执行这一遗传程序的机制尚不清楚。本应用中提出的研究主要围绕Foxp3如何与靶基因结合，以及Foxp3如何抑制或诱导这些位点的转录等基本问题。拟议的研究将大大增加我们对Foxp3如何调节基因表达的理解，从这些研究中获得的信息将与设计新的治疗策略相关，通过这些策略可以促进人类的耐受性。

DESCRIPTION (provided by applicant): Regulatory T cells are crucial for the control of immune-mediated pathology during organ transplant rejection and autoimmune disease, therefore understanding the underlying mechanisms by which these cells function will be critical for promoting immune tolerance in humans. Recent studies in experimental models have established that Foxp3, which is a member of the forkhead family of DNA binding proteins, is necessary and sufficient for specification of regulatory T lymphocyte lineage choice and function. and therefore is crucial for acquired immune tolerance. Expression of Foxp3 initiates a unique transcriptional program which includes the induction of genes such as GITR, CD25, CTLA-4, IL-10 and TGF2, and repression of pro-inflammatory cytokine genes such as IL-2 and IFN?. The mechanisms by which Foxp3 enforces this genetic program are unclear. The studies proposed in this application are centered around basic questions of how Foxp3 binds to target genes, and how Foxp3 represses or induces transcription at these loci. The proposed studies will add significantly to our understanding of how Foxp3 regulates gene expression, and the information gained from these studies will have relevance for the design of novel therapeutic strategies by which tolerance can be promoted in humans.