IPEX and Scurfin/FoxP3: Dysregulation of T cells

描述（由申请人提供）：自身免疫是由正常耐受机制的破坏引起的，该机制允许免疫系统适当调节对自身抗原的反应。通过对小鼠模型系统的研究，在对人类自身免疫性疾病的理解方面取得了进展。一个这样的系统是X连锁皮屑（sf）突变体，其中受影响的男性发展为严重的自身免疫性淋巴组织增生性疾病，在20-24天内是致命的。最初的实验表明，这些症状是体内T细胞慢性活化的结果，伴随着各种细胞因子的过度产生。在这些小鼠中发生突变的基因已经被克隆出来，并被证明是叉头/翼状螺旋家族的成员，现在被称为FOXP 3。Scurfin（FOXP 3编码的蛋白质）的初步生物化学分析表明，它是一种转录抑制因子，作用于受NF-AT和AP-1调控的基因。来自过表达该基因的小鼠的T细胞在体外TCR刺激时不能增殖或产生细胞因子，并且也不能对体内免疫攻击作出应答。该基因的人类同源物也已被鉴定，并显示在免疫失调/多内分泌病/肠病/X连锁（IPEX）综合征中发生突变，其中受影响的男性发展为各种自身免疫性疾病，包括IDDM，并在第一年死亡。总的来说，这些数据与Scurfin在调节T细胞对抗原刺激的应答中的作用一致。我们的模型提出，T细胞中Scurfin的水平起作用，为TCR参与后的功能性T细胞活化设定阈值。皮屑小鼠缺乏Scurfin导致对自身抗原的耐受性中断，这是由于T细胞活化的阈值降低。另一方面，Scurfin在T细胞中的过表达提高了功能活化的阈值，使得这些细胞对TCR接合无应答。然而，Scurfin调节自身耐受性的机制仍然未知。本申请中的实验旨在深入了解Scurfin调节正常和致病性T细胞活化的能力。这些分析将揭示参与自身免疫性疾病发展的调节途径，并将作为人类免疫系统异常的模型。

DESCRIPTION (provided by applicant): Autoimmunity results from a breakdown in the normal tolerance mechanisms that allow the immune system to properly regulate responses to self-antigens. Progress has been made in the understanding of human autoimmune diseases through the study of mouse model systems. One such system is the X-linked scurfy (sf) mutant, where affected males develop a severe autoimmune lymphoproliferative disease that is fatal by 20-24 days of age. Initial experiments have shown that these symptoms are the result of chronic in vivo T cell activation, with overproduction of a wide variety of cytokines. The gene that is mutated in these mice has been cloned and shown to be a member of the forkhead/winged-helix family, now known as FOXP3. Initial biochemical analysis of Scurfin (the protein encoded by FOXP3) has shown that it is a transcriptional repressor, acting on genes regulated by NF-AT and AP-1. T cells from mice that overexpress this gene fail to proliferate or produce cytokines upon TCR stimulation in vitro, and also fail to respond to immunological challenge in vivo. The human homolog of this gene has also been identified and shown to be mutated in the Immune dysregulation/Polyendocrinopathy/Enteropathy/X-linked (IPEX) syndrome, where affected males develop a variety of autoimmune diseases, including IDDM, and die in their first year. Taken as a whole, these data are consistent with a role for Scurfin in the regulation of T cell responses to antigenic stimulation. Our model proposes that levels of Scurfin in T cells act to set a threshold for functional T cell activation following TCR engagement. Lack of Scurfin in scurfy mice causes a break in tolerance to self antigens due to a lowered threshold for T cell activation. On the other hand, overexpression of Scurfin in T cells raises the threshold for functional activation such that these cells are non-responsive to TCR engagement. However, the mechanism by which Scurfin regulates self-tolerance remains unknown. The experiments in this application are designed to provide insight into the ability of Scurfin to regulate the activation of normal and pathogenic T cells. These analyses will shed light on the regulatory pathways involved in the development of autoimmune disease, and will serve as a model for human immune-system abnormalities.