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到调节区分自我和非我的能力的机制的失败。调节自身耐受性的主要方法是通过删除胸腺中的自我反应细胞。然而，这种机制并不完美，自动反应克隆确实会逃逸到外围。外周耐受是通过各种机制产生的，包括T细胞无能和T细胞冷漠或无知。最近，另一种更活跃的耐受诱导机制已经被发现，它是由一群调节性T细胞控制的，这些调节性T细胞积极地抑制自身反应性T细胞的功能。这些被称为Treg细胞的T细胞在阻止对自身抗原的反应方面发挥着关键作用，因为在没有它们的情况下会形成致命的自身免疫。然而，这些细胞执行任务的机制尚不清楚。最近的研究表明，Forkhead/Winged-Helix蛋白FOXP3主要在Treg细胞中表达，对其发育和功能是必要和充分的。Foxp3作为转录调节因子，靶向在刺激的CD4+T细胞中诱导表达的细胞因子基因。我们已经发现了更多与FOXP3相互作用并调节其功能的蛋白质。其中一种被称为FIK(FOXP3相互作用KRAB结构域蛋白)，在人而不是小鼠的Treg中发现，它是编码人ZFP90的mRNA的Treg特异性选择性剪接的结果。FIK反过来与KAP1相互作用，KAP1是一个连接FOXP3和抑制性染色质重塑复合体的适配器。我们有初步数据表明，破坏这些复合体会导致Treg抑制因子功能的丧失和Treg基因表达的丧失，否则Treg基因会被抑制。本方案中的实验将涉及：1.FOXP3-FIK-KAP1复合体在调节人类Treg基因表达中的作用；2.FOXP3-FIK-KAP1复合体在调节人类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 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.