The Role of the Adenosine Receptor in Th Cell Development and Function

摘要/摘要 免疫动态平衡反映了宿主反应和抗原环境之间的平衡。 在粘膜免疫学中，炎症性肠病(IBD)，包括溃疡性结肠炎或克罗恩病， 通过夸大宿主对当地微生物区系的遗传反应来反映动态平衡的破坏 易受感染的宿主。我们的微生物群落是动态的，所以调节外围诱导的Th细胞 (PTreg)对于与这些不同的生物保持灵活的动态平衡很重要。许多因素修改了 维持动态平衡和Treg功能的代谢平衡。与这一提议相关的研究已经 在人类和动物模型中，腺苷代谢障碍与IBD有关。腺苷是一种 在CD73继续的同时，CD39通过将ATP转化为ADP和5‘AMP而产生的嘌呤代谢物 代谢为腺苷。由于死亡细胞或细菌产生的三磷酸腺苷是促炎的，其 分解代谢为腺苷是抑制炎症的一种手段。腺苷具有直接抗炎作用 主要由淋巴细胞表达的A2A型腺苷受体(A2AAR)介导的特性 作为抗原提呈细胞和先天淋巴样细胞。此外，我们提出了新的发现，表明 腺苷改变Th细胞的能量代谢，以发挥其抗炎作用。其他数据 表明腺苷的缺乏启动了致病Th细胞的扩张，Treg的减少，以及 选择传播结肠炎易感性的微生物区系。这项研究的假设是腺苷是 维持消化道的免疫平衡所必需的。更具体地说，扰乱腺苷 生产或反应影响淋巴样细胞的命运，进而改变细菌的定植， 造成了生物失调，促进了炎症。该项目的总体目标是确定 嘌呤代谢对肠道免疫稳态的控制作用，如下所述 相互关联的具体目标： 目的1：确定淋巴微生物动态平衡如何依赖于腺苷。 目标2：确定腺苷如何控制对微生物区系的保护性反应 目的3：明确嘌呤代谢在控制淋巴样细胞命运中的作用。。 拟议中的实验将探索免疫动态平衡的新方面。这些研究将 对淋巴细胞可塑性的基本认识有积极的影响，并提供新的知识 可用于加速识别和开发免疫介导的治疗策略 疾病。

ABSTRACT/SUMMARY Immunological homeostasis reflects a balance between the host response and the antigenic environment. In mucosal immunology, inflammatory bowel diseases (IBD), including ulcerative colitis or Crohn’s disease, reflect a disruption in homeostasis with exaggerated host responses to the local microbiota in genetically susceptible hosts. Our microbial communities are dynamic so regulatory Th cells induced in the periphery (pTreg) are important to maintain a flexible homeostasis with these diverse organisms. Many factors modify the metabolic balance that maintains homeostasis and Treg function. Relevant to this proposal, studies have associated a disruption in adenosine metabolism with IBD in humans and in animal models. Adenosine is a purine metabolite derived from ATP through its conversion to ADP and 5’AMP by CD39 while CD73 continues the metabolism to adenosine. As the production of ATP from dead cells or bacteria is pro-inflammatory, its catabolism to adenosine is one means to restrict inflammation. Adenosine has direct anti-inflammatory properties mediated primarily through the A2A adenosine receptor (A2AAR) expressed by lymphocytes as well as antigen presenting cells and innate lymphoid cells. Moreover, we present new findings suggesting that adenosine shifts the energy metabolism in Th cells in order to confer its anti-inflammatory effects. Other data show that the absence of adenosine initiates the expansion of pathogenic Th cells, a decrease in Treg, and selects for microbiota that transmit susceptibility to colitis. The hypothesis for this study is that adenosine is required to maintain immunological homeostasis in the digestive tract. More specifically, disrupting adenosine production or responsiveness impacts lymphoid cell fate that subsequently changes bacterial colonization, creates a dysbiosis and promotes inflammation. The broad objective of the project is to define the role of purine metabolism on the control of immunological homeostasis in the gut as addressed in the following interrelated Specific Aims: Aim 1: Identify how lymphoid-microbial homeostasis relies on adenosine. Aim 2: Determine how adenosine controls protective responses to microbiota Aim 3: Define the role of purine metabolism in controlling lymphoid cell fate. . The proposed experiments will explore novel aspects of immunological homeostasis. These studies will have a positive impact on the basic understanding of lymphoid cell plasticity and provide new knowledge that can be used to expedite the identification and development of therapeutic strategies for immune-mediated diseases.