Tolerance Through Induction of Regulatory T Cells

调节性CD4T细胞(Treg)在自身免疫的预防和维持中起关键作用 同种异体移植耐受。例如，在肠道中，Treg阻止效应器T细胞安装破坏性的 对多种非致病细菌抗原的炎症反应。自然的Treg出现在胸腺 表现为活化细胞的CD45RBLo表型特征。也可以诱导Treg，例如， 在抗原提呈细胞和细胞因子存在的情况下，通过体外或体内激活外周T细胞 通过口服抗原。然而，通常还不清楚这些Treg是否最初是作为先前存在的产物而出现的 CD45RBLo群体内的Treg与来自幼稚的CD45RBHi效应细胞的从头生成。 最近的研究结果表明，后者是可能的，至少在特殊情况下是可能的。如果特雷格可以 诱导后，我们可以描述从效应细胞向Treg分化所涉及的信号。这 将具有重要的临床意义，因为这种转换代表着免疫反应的转变 从免疫到宽容。此外，CTLA-4的上调伴随着Foxp3，a的诱导 转录因子是Treg发育的关键。这些变化发生在体外分离的T细胞和 缺乏T细胞激活。初步数据表明，该单抗可预防CD45RBHI引起的IBD 通过诱导Treg功能产生效应器，提示α-CD45RB启动效应细胞从头转换 在没有T细胞激活的情况下转化为Treg。 在项目2中，我们的目标是确定这些新的Treg信号的作用机制(S)并描绘出 导致Foxp3和CTLA-4的诱导。这是本PPG主题的核心，其目的是定义 外周耐受机制。 在目标1中，我们将定义从头开始的Treg预防IBD的机制。除了分泌物 抑制性细胞因子我们假设它们通过CTLA-4/B7抑制APC和T效应细胞 互动。我们将比较CTLA-4/B7和Foxp3在诱导和自然表达中的作用 特雷格。由于只有一小部分经α-CD45RB处理的细胞表达CTLA-4，在目标2中，我们将定义 伴随细胞质CTLA-4表达的表面标志可进一步识别调节细胞 在人口中。在目标3中，我们将定义导致Treg诱导的信号通路。 这些研究将为Treg的免疫生物学和导致其发生的途径提供新的见解 归纳法。反过来，这将为诱导耐受和预防自身免疫提供新的靶点。 和移植排斥反应。项目2与此PPG中的其他项目在多个层面上集成。

Regulatory CD4 T cells (Treg) play a key role in the prevention of autoimmunity and maintenance of allograft tolerance. For example, in the gut, Treg prevent effector T cells from mounting a destructive inflammatory response to a myriad of non-pathogenic bacterial antigens. Natural Treg arise in the thymus and exhibit a CD45RBLo phenotype characteristic of activated cells. Treg can also be induced, for example, by activation of peripheral T cells in vitro in the presence of Antigen Presenting Cells plus cytokines or in vivo by oral antigen. However, it is generally unclear whether these Treg primarily arise as an outgrowth of preexisted Treg within the CD45RBLo population vs. de novo generation from naive CD45RBHi effector cells. Recent findings suggest that the latter is possible, at least in specialized circumstances. If Treg can be induced de novo, we can delineate the signals involved in differentiation from effector cells to Treg. This would have important clinical implications since this conversion represents a shift in the immune response from immunity to tolerance. Moreover, CTLA-4 upregulation is accompanied by induction of Foxp3, a transcription factor key for Treg development. These changes occur in vitro in isolated T cells and in the absence of T cell activation. Preliminary data reveal that this mAb can prevent IBD caused by CD45RBHI effectors by inducing Treg function, suggesting that alpha-CD45RB initiates de novo conversion of effector cells into Treg in the absence of T cell activation. In Project 2 we aim to determine the mechanism(s) of action of these novel Treg and delineate signals leading to Foxp3 and CTLA-4 induction. This is central to the theme of this PPG, which aims to define peripheral mechanism of tolerance. In Aim 1, we will define the mechanisms by which de novo Treg prevent IBD. In addition to secretion of suppressive cytokines we hypothesize that they inhibit both APCs and T effector cells through CTLA-4/B7 interactions. We will compare the role of CTLA-4/B7 and Foxp3 expression by both induced and natural Treg. Since only a subpopulation of alpha-CD45RB -treated cells expresses CTLA-4, in Aim 2 we will define surface markers that accompany cytoplasmic CTLA-4 expression that can further identify regulatory cells within the population. In Aim 3, we will define the signaling pathways that lead to Treg induction. These studies will provide novel insight into the immunobiology of Treg and the pathways leading to their induction. In turn, this will provide new targets for tolerance induction and the prevention of autoimmunity and transplant rejection. Project 2 integrates with other projects in this PPG on multiple levels.