Effect of IPEX mutations on FOXP3 DNA binding and chromatin remodeling

带有foxpS基因突变的人类患有一种自身免疫性疾病复合体(IPEX)，这种疾病 由于缺乏调节性T淋巴细胞，并导致这些患者最终在 童年。最近对实验模型的研究表明，FoxpS是 Forkhead家族的DMA结合蛋白是调节T的规范的必要条件和充分条件 淋巴细胞系的选择和功能，因此对获得性免疫耐受至关重要。表达式 T淋巴细胞对FoxpS的诱导导致与耐受相关的基因的诱导和抑制 导致炎症和免疫病理的基因。FoxpS导致这种情况的机制 然而，遗传程序尚不清楚。调节性T细胞也被认为是抑制作用的关键 在器官移植过程中的同种异体免疫反应，并被牵连到控制 自身免疫性疾病。自身免疫性疾病或器官疾病患者治疗的重要目标 移植是为了诱导免疫耐受，并对其机制有一个基本的了解 这一过程很可能是这些疾病临床治疗成功的先决条件。这些研究 在本申请中提出的是围绕FoxpS转录生物学的基本问题，并将 显著增加了我们对FoxpS如何调节基因表达和促进耐受性的理解。一个 这些研究的中心原则是，IPEX患者中FoxpS突变的区域是基本的 FoxpS功能的各个方面，以及这里的研究旨在确定这些功能。这个 从这些研究中获得的信息同样将导致新的治疗策略，耐受性 可在自身免疫性疾病患者和器官移植患者中推广。

Humans with mutations in the foxpS gene suffer from a complex of autoimmune disorders (IPEX) that results from the lack of regulatory T lymphocytes, and leads to the eventual death of these patients in childhood. Recent studies in experimental models have established that FoxpS, which is a member of the forkhead family of DMA 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 FoxpS by T lymphocytes leads to the induction of genes associated with tolerance, and to the repression of genes that cause inflammation and immune pathology. The mechanisms by which FoxpS induces this genetic program, however, are not known. Regulatory T cells are also thought to be crucial for the inhibition of alloimmune responses during organ transplantation, and have been implicated in the control of autoimmune disease. An important goal in the treatment of patients with autoimmune disorders or organ transplants is to induce immunologic tolerance, and a basic understanding of the mechanisms that underly this process will likely be a prerequisite for the successful clinical treatment of these diseases. The studies proposed in this application are centered around basic questions of FoxpS transcriptional biology, and will add significantly to our understanding of how FoxpS regulates gene expression and promotes tolerance. A central tenet of these studies is that the regions of FoxpS mutated in IPEX patients are required for basic aspects of FoxpS function, and the studies herein are designed to determine these functions. The information gained from these studies will likewise lead to novel therapeutic strategies by which tolerance can be promoted in patients with autoimmune disease and organ transplants.