Cbl-b in T Cell Activation and Autoimmunity

描述(申请人提供)：自身免疫性疾病是由于免疫系统不能对自身蛋白质产生耐受性而引起的。抗原受体和共刺激受体的信号阈值决定了对自身蛋白的免疫或耐受。一种主要的共刺激受体CD28是在几种小鼠模型中诱导自身免疫所必需的。CD28共刺激放大早期和晚期T细胞受体(TCR)介导的信号事件。已有研究表明，阻断CD28介导的共刺激可能是一种潜在的抗自身免疫的免疫疗法。然而，在体内维持对自身抗原的免疫耐受以及整合共刺激信号和TCR信号的分子机制尚不清楚。最近的研究表明，CD28共刺激可能降低T细胞激活所需的阈值。Casitas-B系淋巴瘤-b蛋白(Cbl-b)是一种连接蛋白和E3泛素连接酶，可以通过调节Vav活性来控制CD28依赖的T细胞的激活，提示Cbl-b在调节T细胞激活阈值从而维持免疫与耐受之间的平衡中起着关键作用。缺乏Cbl-b的小鼠会自发产生自身免疫或增加对实验性变态反应性脑脊髓炎的易感性。因此，Cb1-b可以设定T细胞活化的阈值。我们的初步实验表明，较高剂量的抗CD3刺激部分克服了CD28缺陷小鼠中有缺陷的T细胞增殖。此外，CD28的存在或缺失可能控制TCR诱导的Cbl-b泛素化和降解。这些发现为CD28共刺激如何介导最佳T细胞激活提供了一种新的分子机制(S)。基于以上数据，我们假设Cbl-b调节CD28介导的T细胞激活。具体地说，我们将研究CD28共刺激是否以及如何控制Cbl-b的泛素化；Cbl-b是否调节CD28介导的免疫突触的形成；以及Cbl-b是否调节自身免疫性关节炎中CD28依赖的自身反应性T细胞的激活。建议研究产生的信息将有助于更好地了解Cbl-b在T细胞生物学和自身反应性T细胞反应中的作用，并将有助于开发治疗自身免疫性关节炎的新方法。

DESCRIPTION (provided by applicant): Autoimmune diseases result from the failure of the immune system to develop tolerance to self-proteins. The signaling threshold of antigen receptors and costimulatory receptors determine immunity or tolerance to self-proteins. A major costimulatory receptor, CD28, is required for induction of autoimmunity in several mouse models. CD28 costimulation amplifies early and late T cell receptor (TCR)-mediated signaling events. It has been shown that blocking CD28-mediated costimulation may represent one potential immunotherapy against autoimmunity. However, the molecular mechanisms that maintain immune tolerance to self-antigen in vivo and integrate costimulatory signals with the TCR signals are poorly understood. Recent studies suggest that CD28 costimulation may lower the threshold needed for T cell activation. Casitas-B-lineage lymphoma-b protein (Cbl-b), an adaptor protein and E3 ubiquitin ligase, can control CD28-dependent T cell activation via the regulation of Vav activity, suggesting a critical role of Cbl-b in the regulation of T cell activation threshold and hence in the maintenance of a balance between immunity and tolerance. Mice lacking Cbl-b spontaneously develop autoimmunity or have an increased susceptibility to experimental allergic encephalomyelitis. Therefore, Cbl-b may set the threshold for T cell activation. Our preliminary experiments showed that stimulation with higher doses of anti-CD3 partially overcomes defective T cell proliferation in CD28-deficient mice. Moreover, the presence or absence of CD28 may control TCR-induced Cbl-b ubiquitination and degradation. These findings provide a novel molecular mechanism(s) for how CD28 costimulation mediates optimal T cell activation. Based upon the above data, we hypothesize that Cbl-b regulates CD28-mediated T cell activation. Specifically, we will investigate whether and how CD28costimulation controls ubiquitination of Cbl-b; whether Cbl-b regulates CD28-mediated formation of immunological synapse; and whether Cbl-b regulates CD28-dependent autoreactive T cell activation in autoimmune arthritis. The information generated by the proposed studies will lead to a better understanding of Cbl-b in T cell biology and in autoreactive T cell responses, and will shed light on the development of novel therapeutic approaches to autoimmune arthritis.