The Role of Adenosine Receptors in Th Cell Development and Function

腺苷受体在 Th 细胞发育和功能中的作用

• 批准号: 7690990
• 负责人: Peter B. Ernst
• 金额: $ 37.8万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7690990
• 关键词: Address; Adenosine; Adenosine A2A Receptor; Adoptive Transfer; Age; Agonist; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Area; Bacteria; Basic Science; Cell Death; Cell physiology; Cells; Chronic; Colitis; Colon; Complex; Dendritic Cells; Development; Disease; Down-Regulation; Enteral; Enterobacteriaceae; Enzymes; Etiology; Exposure to; Fibrinogen; Funding; Gastrointestinal tract structure; Generations; Genus Cola; Helicobacter hepaticus; Human; Hypoxia; Immune; Immune Tolerance; Immune response; Immunofluorescence Immunologic; Immunology; In Vitro; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Intestines; Kinetics; Knockout Mice; Knowledge; Life; Mediating; Mediator of activation protein; Messenger RNA; Modeling; Mus; Neonatal; Pathogenesis; Phenotype; Protein Dephosphorylation; Purinergic P1 Receptors; Reaction; Regulation; Relapse; Reporting; Rest; Risk; Role; Series; Subfamily lentivirinae; System; T-Cell Activation; T-Cell Development; T-Lymphocyte; Tissues; Transduction Gene; Weaning; Withdrawal; base; concept; immunological synapse; in vivo; inhibitor/antagonist; innovation; interest; microorganism antigen; mouse model; novel; protein expression; response

Immunological tolerance reflects complex interactions amongst multiple cells and it is tailored to specific challenges that arise during development. For example, in the digestive tract, Th cells limit the host response to dietary or microbial antigens that are introduced into the lumen during neonatal life. The importance of appropriate immune responses to enteric flora is illustrated in mouse models in which Helicobacter hepaticus induces regulatory Th cells (Treg) in normal mice while exacerbating intestinal inflammation in animals in which regulatory T cell function is perturbed. Studies suggest that chronic, relapsing inflammatory bowel diseases (IBD) in humans result from inappropriately regulated immune responses to enteric antigens in genetically susceptible hosts. The exact etiology and pathogenesis of IBD is unclear but there is substantial interest in the role of ¿natural¿ or ¿acquired¿ Treg in intestinal immune regulation. Therefore, it is essential to understand the factors regulating the development of tolerance to luminal flora during the neonatal period as they may influence the risk of developing IBD later in life. One factor that mediates anti-inflammatory activity is adenosine. Adenosine accumulates in inflamed or hypoxic tissues largely due to CD39 mediating the dephosphorylation of ATP to ADP then to 5¿-AMP while CD73 catalyzes the terminal reaction to convert 5¿AMP to adenosine. Activation of A2A adenosine receptors (A2AAR) on T cells produces a series of responses that have been categorized as anti-inflammatory. Our lab discovered that regulatory T cells controlling inflammatory responses in the colon are directly dependent on the presence of the A2AAR. We propose the general hypothesis that adenosine accumulates during Th cell activation and regulates the function of both Treg and effector Th subsets. More specifically, we suggest that the development of acquired tolerance during the post-weaning period is modulated by the A2AAR expressed by Th cells. The objective of this proposal is to understand the untested and novel concept that A2AAR contribute to the development of T cells ¿ such as acquired Treg - that confer immune tolerance. The specific aims are: Aim 1. Define the effects of adenosine accumulation on the function of Th cell subsets. Aim 2. Examine the role of the A2A adenosine receptor in Th cell development. Together, these studies will investigate an innovative and complementary model for the control of effector T cell function that can be exploited pharmacologically for the treatment of chronic inflammatory diseases such as IBD.

免疫耐受性反映了多个细胞之间的复杂相互作用，并且量身定制为特定 发展过程中出现的挑战。例如，在消化道中，TH细胞限制了宿主响应 在新生儿寿命中引入管腔中的饮食或微生物抗原。重要性 在helicobacter Hepaticus的鼠标模型中说明了对肠菌群的适当免疫调查 在正常小鼠中诱导调节性TH细胞（TREG），同时加剧动物的肠道注射 调节性T细胞功能受到干扰。研究表明，慢性传递炎症性肠病 （IBD）在人类中，由于不适当调节的免疫反应，以进入一般的抗原 易感宿主。 IBD的确切病因和发病机理尚不清楚，但对 自然或获得的treg在肠道免疫调节中的作用。因此，必须了解 在新生儿期间调查对腔植物群体耐受性发展的因素 影响生命后期发展IBD的风险。介导抗炎活性的一个因素是 腺苷。腺苷在发炎或低氧组织中积聚，主要是由于CD39介导 将ATP的去磷酸化到ADP，然后降至5？AMP，而CD73则催化末端反应转换5 emp 到腺苷。在T细胞上激活A2a腺苷接收器（A2AAR）会产生一系列反应 已被归类为抗炎。我们的实验室发现调节性T细胞控制 结肠中的炎症反应直接取决于A2AAR的存在。我们建议 一般假设是腺苷在细胞激活过程中积累并调节的功能 Treg和效应子TH子集。更具体地说，我们建议获得的发展 在断奶后期的公差由TH细胞表达的A2AAR调节。 该提议的目的是了解A2AAR对未经测试和新颖的概念的贡献 T细胞的发展，例如获得的Treg-赋予免疫耐受性。具体目的是：目标1。 定义腺苷积累对TH细胞子集功能的影响。目标2。检查 A2a腺苷受体在细胞发育中的作用。这些研究将一起研究 可以探索效应的T细胞功能的创新和完整的模型 在药理上用于治疗慢性炎症性疾病，例如IBD。