A FOXP3 complex that controls human regulatory T cell function

描述（由申请人提供）：自身免疫的发展涉及调节区分自我与非自我的能力的机制的失效。主 调节自身耐受性的方法是通过去除胸腺中的自身反应细胞。然而，这种机制并不完美，自反应克隆确实会逃逸到外周。外周耐受是通过多种机制产生的，包括T细胞无反应性和T细胞冷漠或无知。最近，已经鉴定了另一种更活跃的耐受诱导机制，其由主动抑制自身反应性T细胞功能的调节性T细胞群控制。这些T细胞，被称为Treg细胞，在防止对自身抗原的反应方面发挥着关键作用，因为致命的自身免疫性在缺乏它们的情况下发展。然而，这些细胞执行任务的机制尚不清楚。最近的研究表明，叉头/翼状螺旋蛋白FOXP 3主要在Treg细胞中表达，并且对于它们的发育和功能是必要的和足够的。FOXP 3作为转录调节因子，靶向细胞因子基因，其表达在刺激的CD 4 + T细胞中被诱导。我们已经确定了与FOXP 3相互作用并调节其功能的其他蛋白质。其中之一，称为FIK（FOXP 3相互作用KRAB结构域蛋白），发现于人而非鼠TGFP中，并作为编码人ZFP 90的mRNA的Treg特异性选择性剪接的结果而产生。FIK反过来与KAP 1相互作用，KAP 1是连接FOXP 3与抑制性染色质重塑复合物的接头。我们有初步的数据表明，这些复合物的破坏导致Treg抑制功能和表达的基因，否则抑制在TcG的损失。本提案中的实验将解决：1。FOXP 3-FIK-KAP 1复合物在调节人TGF 1基因表达中的作用，和2. FOXP 3-FIK-KAP 1复合物在调节人Treg功能中的作用

DESCRIPTION (provided by applicant): The development of autoimmunity involves the failure of the mechanisms that regulate the ability to discriminate self from non-self. The primary means of regulating self-tolerance is through the deletion of self- reactive cells in the thymus. However, this mechanism is not perfect and auto-reactive clones do escape into the periphery. Peripheral tolerance is generated through a variety of mechanisms including T cell anergy and T cell indifference or ignorance. Recently, another more active mechanism of tolerance induction has been identified that is controlled by a population of regulatory T cells which actively suppress the function of auto- reactive T cells. These T cells, known as Treg cells, play a critica role in preventing responses to self-antigens as fatal autoimmunity develops in their absence. However, the mechanism by which these cells perform their tasks is as yet unclear. Recent work has shown that the forkhead/winged-helix protein FOXP3 is expressed predominantly in Treg cells and is both necessary and sufficient for their development and function. FOXP3 acts as a transcriptional regulator, targeting cytokine genes whose expression is induced in stimulated CD4+ T cells. We have identified additional proteins that interact with FOXP3 and regulate its function. One of these, referred to as FIK (FOXP3 Interacting KRAB domain protein), is found in human but not murine Tregs and arises as a consequence of Treg-specific alternative splicing of the mRNA encoding human ZFP90. FIK in turn interacts with KAP1, an adaptor linking FOXP3 to a repressive chromatin remodeling complex. We have preliminary data showing that disruption of these complex results in loss of Treg suppressor function and expression of genes otherwise repressed in Tregs. The experiments in this proposal will address: 1. The role of the FOXP3-FIK-KAP1 complex in regulating gene expression in human Tregs, and 2. The role of the FOXP3-FIK-KAP1 complex in regulating human Treg function.