Cbl-b in T Cell Activation and Autoimmunity

描述（由申请人提供）：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。在几种小鼠模型中，一种主要的共刺激受体CD28是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。研究表明，阻断cd28介导的共刺激可能是对抗自身免疫的一种潜在免疫疗法。然而，维持体内对自身抗原的免疫耐受并将共刺激信号与TCR信号整合的分子机制尚不清楚。最近的研究表明，CD28共刺激可能会降低T细胞激活所需的阈值。casitas -b谱系淋巴瘤b蛋白（cblb）是一种衔接蛋白和E3泛素连接酶，可以通过调节Vav活性来控制cd28依赖性T细胞的激活，这表明cblb在调节T细胞激活阈值中起关键作用，从而维持免疫和耐受之间的平衡。缺乏clb -b的小鼠会自发产生自身免疫，或对实验性过敏性脑脊髓炎的易感性增加。因此，Cbl-b可能设定了T细胞活化的阈值。我们的初步实验表明，高剂量的抗cd3刺激部分克服了cd28缺陷小鼠的T细胞增殖缺陷。此外，CD28的存在或缺失可能控制tcr诱导的cl -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。基于上述数据，我们假设Cbl-b调节cd28介导的T细胞活化。具体来说，我们将研究cd28共刺激是否以及如何控制cl -b的泛素化；Cbl-b是否调控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依赖性自身反应性T细胞的活化。拟议的研究产生的信息将导致更好地理解ctl -b在T细胞生物学和自身反应性T细胞反应中的作用，并将阐明自身免疫性关节炎的新治疗方法的发展。

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.