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

描述（由申请人提供）：越来越清楚的是，CD 4 T细胞可塑性是启动和调节免疫应答的一个重要方面。在决定T细胞分化命运中起关键作用的因素之一是TGF β。最近的研究表明，TGF β 1通过其诱导Foxp 3和RORγt表达的能力参与iTreg/Th 17分化。CD 4 T细胞在TGF β单独存在下暴露于抗原导致iTreg发育，而炎症细胞因子（例如，IL-6）与TGF β 1导致Th 17分化。因此，TGF β 1基于微环境线索调节Foxp 3和RORγt表达的能力是T细胞功能的关键方面。因此，调节TGF β 1功能的因子在这一过程中是重要的参与者。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，这是Sloan-Kettering逆转录病毒中能够转化鸡胚成纤维细胞的逆转录病毒癌基因。细胞同源物c-Ski已被证明对胚胎发育的几个方面是重要的，并且Ski缺乏导致晚期胚胎死亡。Ski通过靶向几个下游信号传导事件作为TGF β 1信号传导途径的天然抑制剂发挥作用。然而，Ski在免疫系统中的作用尚未确定。鉴于TGF β 1在调节免疫应答中的重要作用，在免疫发育和应答的背景下更好地理解Ski是重要的。对于这项工作，我们已经产生了一个小鼠品系，其中包含Ski的条件性敲除等位基因，使我们能够在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，本提案的目的是：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细胞功能的影响。

DESCRIPTION (provided by applicant): 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 TGFß. Recent work has shown that TGFß, through its ability to induce the expression of both Foxp3 and RORγt, is involved in iTreg/Th17 differentiation. Exposure of CD4 T cells to antigen in the presence of TGFß alone leads to iTreg development, while the presence of inflammation cytokines (e.g., IL-6) with TGFß results in Th17 differentiation. Thus, the ability of TGFß to regulate the expression of Foxp3 and RORγt based on microenvironmental cues, is a key aspect of T cell function. Factors that regulate TGFß 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 TGFß 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 TGFß 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 wll 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 TGFß-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.