The Role of Adenosine Receptors in Th Cell Development and Function

描述（由申请人提供）：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，包括那些在新生儿时期引入管腔的抗原。在小鼠模型中，肝螺杆菌在正常小鼠中诱导调节性T细胞（Treg），而在调节性T细胞功能紊乱的动物中加剧肠道炎症，说明了对肠道微生物群适当免疫反应的重要性。研究表明，人类慢性复发性炎症性肠病（IBD）是由遗传易感宿主对肠道抗原的免疫反应调节不当引起的。然而，很少有研究调查断奶后肠道微生物群耐受性的发展，但这段时间的反应可能会影响以后患IBD的风险。IBD的确切病因和发病机制尚不清楚，但人们对“天然”或“适应性”Treg在肠道免疫调节中的作用非常感兴趣。介导抗炎活性的一个因素是腺苷。在炎症或缺氧组织中，腺苷的积累主要是由于CD39介导ATP的去磷酸化转化为ADP，然后转化为5'-AMP，而CD73催化末端反应将5' amp转化为腺苷。激活Th细胞上的A2A腺苷受体（A2AAR）会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，Treg被报道表达CD39和CD73，并通过合成腺苷增强Treg的功能。我们提出Treg表达腺苷合成所需的酶和这种介质有助于控制炎症的一般假设。具体来说，我们假设断奶后耐受的发展是由来源于Treg的腺苷促成的。本提案的目的是评估腺苷如何促进Treg在整个断奶后时期对肠道微生物群的耐受性。具体目标是：目标1。描述腺苷在断奶后时期细胞发育中的作用。目标2。测定细胞亚群合成腺苷和对腺苷作出反应的能力。目标3。描述腺苷调节细胞反应的机制。总之，这些研究将使用新的动物模型和药理学试剂来研究控制效应细胞功能的创新和互补模型。有了这一新的信息，腺苷受体激动剂可能在药理学上被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. PUBLIC HEALTH RELEVANCE: This proposal will examine the physiological role by which adenosine receptors impact the development of immune tolerance that inhibits pathogenic T cell responses to bacteria found in the intestinal lumen. Establishing a novel role for adenosine and its receptors in this process is not only a completely new direction for understanding the biology of Treg, but it will lead to future translational studies in humans that model the induction of long-term antigen-specific immune tolerance. This new information may have therapeutic applications for the prevention or treatment of inflammatory bowel diseases and possibly other illnesses that can be controlled by regulatory T cells.