The Role of Adenosine Receptors in Th Cell Development and Function

描述(申请人提供)：免疫耐受性反映了多个细胞之间复杂的相互作用。在消化道中，Th细胞限制宿主对饮食或微生物抗原的反应，包括那些在新生儿生命期间被引入管腔的抗原。在小鼠模型中，适当的肠道微生物区系免疫反应的重要性被阐明，在该模型中，肝螺杆菌诱导正常小鼠的调节性Th细胞(Treg)，同时加剧调节性T细胞功能受扰的动物的肠道炎症。研究表明，人类慢性复发性炎症性肠病(IBD)是由于遗传易感宿主对肠道抗原的免疫反应调节不当所致。然而，很少有研究研究在断奶后阶段对管腔微生物群的耐受性的发展，但在这段时间内的反应可能会影响日后发展为IBD的风险。IBD的确切病因和发病机制尚不清楚，但人们对“自然”或“适应性”Treg在肠道免疫调节中的作用有很大兴趣。介导抗炎活性的一个因素是腺苷。腺苷在炎症或缺氧组织中的积聚主要是由于CD39介导了ATP的脱磷酸化为ADP，然后是5‘-AMP，而CD73则催化了5’-AMP转化为腺苷的末端反应。激活Th细胞上的A2AAR(A2AAR)可产生一系列被归类为抗炎的反应。我们的实验室发现，Th细胞表达A2AAR是最佳Treg功能所必需的。随后，有报道Treg表达CD39和CD73，并通过合成腺苷增强Treg功能。我们提出的一般假设是，Treg表达腺苷合成所需的酶，这种介质有助于控制炎症。具体地说，我们假设，在断奶后阶段，Treg来源的腺苷有利于耐受性的发展。这项建议的目的是评估腺苷如何有助于Treg在整个断奶后阶段向肠道微生物群授予耐受性。具体目标是：目的1.研究腺苷在断奶后Th细胞发育中的作用。目的2.测定Th细胞亚群合成腺苷的能力及对腺苷的反应性。目的3.研究腺苷调节Th细胞反应的机制。总之，这些研究将使用新的动物模型和药理试剂来探索一种控制效应器Th细胞功能的创新和补充模型。有了这一新信息，腺苷受体激动剂可能被药理学地开发用于治疗慢性炎症性疾病，如IBD。

DESCRIPTION (provided by applicant): Immunological tolerance reflects complex interactions amongst multiple cells. In the digestive tract, Th cells limit the host response to dietary or microbial antigens including those that are introduced into the lumen during neonatal life. The importance of appropriate immune responses to enteric microbiota 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. However, few studies have examined the development of tolerance to luminal microbiota during the post-weaning period but the responses during this time may affect the risk of developing IBD later in life. The exact etiology and pathogenesis of IBD is unclear but there is substantial interest in the role of "natural" or "adaptive" Treg in intestinal immune regulation. 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 Th cells produces a series of responses that have been categorized as anti-inflammatory. Our lab discovered that the expression of the A2AAR by Th cells is required for optimal Treg function. Subsequently, Treg have been reported to express CD39 and CD73 and enhance Treg function by synthesizing adenosine. We propose the general hypothesis that Treg express the enzymes required for adenosine synthesis and this mediator contributes to the control of inflammation. Specifically, we hypothesize that the development of tolerance during the post-weaning period is favored by adenosine derived from Treg. The objective of this proposal is to assess how adenosine contributes to the ability of Treg to confer tolerance to the intestinal microbiota throughout the post-weaning period. The specific aims are: Aim 1. Characterize the role of adenosine in Th cell development during the post-weaning period. Aim 2. Determine the ability of Th cell subsets to synthesize and respond to adenosine. Aim 3. Characterize the mechanisms by which adenosine modulates Th cell responses. Together, these studies will use novel animal models and pharmacological reagents to investigate an innovative and complementary model for the control of effector Th cell function. With this new information, adenosine receptor agonists may be exploited pharmacologically for the treatment of chronic inflammatory diseases such as IBD.