c-Ski and the regulation of CD4 T cell-mediated autoimmunity and tolerance

项目总结/摘要 越来越清楚的是，CD 4 T细胞可塑性是启动和调节免疫的重要方面， 应答在决定T细胞分化命运中起关键作用的因素之一是TGF？。最近 研究表明，TGF β通过其诱导Foxp 3和ROR β t表达的能力，参与了 iTreg/Th 17分化。在单独存在TGF β的情况下，CD 4 T细胞暴露于抗原导致iTreg 发展，而炎症细胞因子的存在（例如，IL-6）与TGF β导致Th 17分化。 因此，TGF β调节Foxp 3和ROR β表达的能力不是基于微环境线索， 是T细胞功能的一个关键方面。因此，调节TGF β功能的因素在这一过程中起着重要作用。 过程一个这样的因子是原癌基因c-Ski。Ski基因最初被鉴定为v-Ski，即逆转录病毒 Sloan-Kettering逆转录病毒中能够转化鸡胚成纤维细胞的癌基因。蜂窝 同源物，c-Ski，已被证明是重要的几个方面的胚胎发育，和Ski， 缺乏导致胚胎晚期死亡。Ski作为TGF β信号通路的天然抑制剂， 针对几个下游信号事件。然而，Ski在免疫系统中的作用还没有被证实。 测定鉴于TGF β在调节免疫反应中的重要作用， 在免疫发展和反应的背景下是重要的。为了这项工作，我们已经产生了一个鼠标 该菌株含有Ski的条件性敲除等位基因，允许我们在T细胞中特异性地删除Ski。这些 小鼠将使我们能够确定Ski在T细胞稳态和功能中的作用。考虑到这一点， 这些建议是：1.确定Ski在调节CD 4 T细胞中TGF β介导的作用中的作用; 2. 确定Ski在调节T细胞稳态中的作用; 3.确定Ski缺乏对CD 4 T的影响 细胞功能

Project Summary/Abstract It is becoming clear that CD4 T cell plasticity is an important aspect of initiating and regulating immune responses. Among the factors that play a critical role in determining T cell differentiative fate is TGF¿. Recent work has shown that TGF¿, through its ability to induce the expression of both Foxp3 and ROR¿t, is involved in iTreg/Th17 differentiation. Exposure of CD4 T cells to antigen in the presence of TGF¿ alone leads to iTreg development, while the presence of inflammation cytokines (e.g., IL-6) with TGF¿ results in Th17 differentiation. Thus, the ability of TGF¿ to regulate the expression of Foxp3 and ROR¿t based on microenvironmental cues, is a key aspect of T cell function. Factors that regulate TGF¿ function are therefore important players in this process. One such factor is the proto-oncogene c-Ski. The Ski gene was first identified as v-Ski, the retroviral oncogene in Sloan-Kettering retroviruses capable of transforming chicken embryo fibroblasts. The cellular homolog, c-Ski, has been shown to be important for several aspects of embryonic development, and Ski- deficiency leads to late embryonic death. Ski functions as a natural inhibitor of the TGF¿ signaling pathway by targeting several downstream signaling events. However, a role for Ski in the immune system has not been determined. Given the important role of TGF¿ in regulating immune responses, a better understanding of Ski in the context of immune development and responses is important. For this work we have generated a mouse strain that contains a conditional knockout allele of Ski, allowing us to delete Ski specifically in T cells. These mice will allow us to determine the role of Ski in T cell homeostasis and function. With this in mind, the aims of this proposal are: 1. Determine the role of Ski in regulating TGF¿-mediated effects in CD4 T cells; 2. Determine the role of Ski in regulating T cell homeostasis; 3. Determine the effect of Ski-deficiency on CD4 T cell function.