A2a receptor engagement promotes T cell tolerance

描述（由申请人提供）：腺苷A2a受体最近被证明在体内负性调节免疫反应中起关键作用。我们的实验室一直对分析促进tcr诱导的激活与耐受性的信号很感兴趣。在我们的研究过程中，我们发现腺苷A2a受体在诱导T细胞能量的过程中高度上调。根据初步数据，我们假设A2a受体与T细胞的结合促进了T细胞耐受的诱导。利用体外T细胞克隆，我们将确定A2a受体激动剂在共刺激环境下促进T细胞耐受性的能力。利用A2a基因敲除小鼠，我们将确定A2a受体促进耐受性的特异性以及内源性腺苷在促进耐受性中的作用。进一步，我们将定义A2a受体在抗原提呈细胞（APCs）和靶组织中的作用。利用T细胞介导的自身免疫的体内模型，我们将证明A2a受体参与通过促进能量和抗原特异性Lag-3+ T调节细胞来防止T细胞介导的死亡的能力。有趣的是，肿瘤微环境中含有高水平的腺苷。因此，我们提出肿瘤来源的腺苷有助于诱导肿瘤特异性T细胞耐受。我们将在一个明确的前列腺癌小鼠模型中使用A2a特异性拮抗剂和来自A2a敲除小鼠的T细胞来验证这一假设。我们预测，通过抑制A2a受体的结合，我们将能够预防/克服肿瘤诱导的耐受性，从而提高肿瘤疫苗的功效。我们还将定义a2a诱导耐受的机制。之前，我们已经证明CREB和CREM与IL-2启动子-180位点的结合在抑制IL-2在无能T细胞中的转录中起重要作用。由于A2a接合导致cAMP的产生，我们将测试A2a接合部分通过增强CREB/CREM在该位点的结合来介导其抑制作用的假设。此外，基于初步数据，我们将验证新的cAMP激活目标EPAC是关键下游效应物的假设。了解A2a受体促进T细胞耐受性的作用和机制将为设计特定的临床靶点提供见解。

DESCRIPTION (provided by applicant): The adenosine A2a receptor has recently been shown to play a critical role in negatively regulating immune responses in vivo. Our laboratory has been interested in dissecting the signals that promote TCR-induced activation versus tolerance. During the course of our studies we have found that the adenosine A2a receptor is highly upregulated during the induction of T cell anergy. Based upon preliminary data we hypothesize that A2a receptor engagement on T cells promotes the induction of T cell tolerance. Using T cell clones in vitro we will define the ability of A2a receptor agonists to promote T cell tolerance even in the setting of costimulation. Using A2a knockout mice we will define the specificity of the A2a receptor in promoting tolerance and the role of endogenous adenosine in promoting tolerance. Further we will define the role of the A2a receptor on antigen presenting cells (APCs) and target tissues. Using an in vivo model of T cell mediated autoimmunity we will demonstrate the ability of A2a receptor engagement to prevent T cell mediated death by promoting anergy and antigen specific Lag-3+ T regulatory cells. Interestingly, the tumor microenvironment contains high levels of adenosine. As such, we propose that tumor-derived adenosine facilitates the induction of tumor-specific T cell tolerance. We will test this hypothesis using A2a specific antagonists and T cells from the A2a knockout mice in a well defined murine model of prostate cancer. We predict that by inhibiting A2a receptor engagement, we will be able to prevent/overcome tumor-induced tolerance and thus enhance the efficacy of tumor vaccines. We will also define the mechanism of A2a-induced tolerance. Previously, we have shown that the binding of CREB and CREM to the -180 site of the IL-2 promoter plays an important role in repressing IL-2 transcription in anergic T cells. In as much as A2a engagement leads to the generation of cAMP, we will test the hypothesis that A2a engagement mediates its inhibitory effect in part by enhancing the binding of the CREB/CREM at this site. Furthermore, based on preliminary data we will test the hypothesis that the novel cAMP activated target EPAC is a critical downstream effector. Understanding the role and mechanism by which the A2a receptor promotes T cell tolerance should provide insight in terms of devising specific clinical targets.