A2a receptor engagement promotes T cell tolerance

A2a 受体结合促进 T 细胞耐受

基本信息

批准号：
7282052
负责人：
JONATHAN D POWELL
金额：
$ 25.44万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7282052
关键词：
Adenosine Adoptive Transfer Agonist Antigen-Presenting Cells Antigens Autoimmunity B-Lymphocytes Binding CD4 Positive T Lymphocytes CD8B1 gene CREB1 gene Cancer Vaccines Cell physiology Cells Cessation of life Clinical Condition Cyclic AMP Data Dendritic Cells Development Dose Generations Genetic Transcription Immune Immune response Immune system In Vitro Incubated Inflammation Interleukin-2 Knockout Mice Laboratories Lead Light Liver Malignant neoplasm of prostate Mediating Mitogen-Activated Protein Kinases Modeling Mus Pathway interactions Play Production Proteins Purinergic P1 Receptors Ras Inhibitor Repression Research Personnel Role Second Messenger Systems Signal Transduction Site Specificity T-Cell Activation T-Lymphocyte Testing Tissues Tumor Antigens Tumor Immunity Tumor-Derived anergy base day design extracellular granzyme A in vitro Model in vivo in vivo Model insight interest macrophage novel perforin prevent programs promoter receptor second messenger tumor

项目摘要

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.

描述（由申请人提供）：腺苷A2A受体最近已显示在负体内负调节免疫反应中起关键作用。我们的实验室感兴趣地解剖促进TCR诱导的激活与耐受性的信号。在研究过程中，我们发现腺苷A2A受体在诱导T细胞消音过程中高度上调。基于初步数据，我们假设T细胞上的A2A受体参与促进了T细胞耐受性的诱导。在体外使用T细胞克隆，我们将定义A2a受体激动剂的能力，即使在共刺激的情况下，也可以定义A2A受体激动剂促进T细胞耐受性。使用A2A基因敲除小鼠，我们将定义A2A受体在促进耐受性和内源性腺苷在促进耐受性中的作用的特异性。此外，我们将定义A2A受体在抗原呈递细胞（APC）和靶组织中的作用。使用T细胞介导的自身免疫的体内模型，我们将证明A2A受体参与度通过促进厌食和抗原特异性滞后-3+ T调节细胞来防止T细胞介导的死亡的能力。有趣的是，肿瘤微环境含有高水平的腺苷。因此，我们建议肿瘤衍生的腺苷有助于诱导肿瘤特异性T细胞耐受性。我们将使用A2A特异性拮抗剂和来自A2A基因敲除小鼠的T细胞在前列腺癌的鼠模型中检验该假设。我们预测，通过抑制A2A受体的参与度，我们将能够预防/克服肿瘤诱导的耐受性，从而增强肿瘤疫苗的功效。我们还将定义A2A诱导的公差的机制。以前，我们已经表明，CREB和CREM与IL-2启动子的-180位点的结合在抑制Anergic T细胞中IL-2转录方面起着重要作用。在A2A的参与度中，我们将测试A2A参与度介导其抑制作用的假设，部分通过增强了该站点的CREB/CREM的结合。此外，基于初步数据，我们将检验以下假设：新型CAMP激活的目标EPAC是关键的下游效应子。了解A2A受体促进T细胞耐受性的作用和机制应在设计特定的临床靶标方面提供见解。