The Role of the Aryl Hydrocarbon Receptor in Intestinal Immunity

说明（由申请人提供）：人体免疫系统必须保持恒定的平衡才能健康。对抗有害微生物需要提高免疫反应，但同样的反应必须防止过度反应和攻击身体的正常组织。已知一种复杂的免疫细胞组合会影响这种平衡。其中，Th17细胞是一种新定义的T细胞亚群（一组白细胞），对清除某些细菌或真菌感染很重要，而Th17反应失调可导致许多人类自身免疫性疾病，如炎症性肠病（IBD）。已经发现调节性T细胞（Treg）可以控制包括Th17细胞在内的效应T细胞的有害作用。受转录因子相互作用影响的Th17和Treg细胞之间的平衡在肠道环境中最为明显，对维持肠道免疫稳定至关重要。芳烃受体（AhR）是Th17细胞中表达上调最多的转录因子之一，以介导环境毒素的作用而闻名。AhR促进Th17细胞分化，也可能参与Treg分化，从而调节Th17-Treg平衡。AhR可以被环境毒素和正常生活在肠道中的细菌产生的天然化合物激活。因此，确定AhR在Th17生物学中的作用将为环境因素、肠道微生物群和人类免疫疾病之间提供一个有趣的联系，但AhR在感染和炎症中的确切作用仍有待确定。我的长期研究目标是致力于确定调节炎症和抗炎细胞平衡的分子手段，从而对抗感染和预防自身免疫。在本提案中，我们将验证一个新的假设，即AhR通过影响Th17和Treg细胞的分化在肠道免疫中起关键作用，AhR对个体Th17细胞因子表达的差异影响可能影响IBD的发病机制。将采用模拟人类IBD的小鼠慢性结肠炎T细胞转移模型。我们将利用功能丧失和功能获得的方法，通过追求以下三个具体目标来验证这一假设：1)表征ahr缺陷T细胞诱导的结肠炎。2)确定减弱Th1或Th17反应是否可以改善ahr缺陷T细胞转移介导的结肠炎。3)确定AhR在Treg分化及结肠炎发病中的作用。从我们提出的研究中获得的知识将阐明如何调节转录因子的活性以维持肠道免疫系统的稳定性，从而预防各种使人衰弱的疾病。由于AhR的激活需要与某些分子（即配体）结合，因此本项目的结果可能使我们能够确定新的药物靶点并开发小化合物来调节AhR活性，以用于人类免疫疾病的治疗干预。

DESCRIPTION (provided by applicant): The human immune system must remain in constant balance to be healthy. Elevated immune responses are needed to fight harmful microorganisms, yet those same responses have to be kept from overreacting and attacking the body's normal tissues. A complex mix of immune cells is known to influence this balance. Among them, Th17 cells, a newly defined T cell subset (a group of white blood cells), are important to clear certain bacterial or fungal infections, whereas dysregulated Th17 responses can cause many human autoimmune diseases, such as inflammatory bowel disease (IBD). Regulatory T cells (Treg) have been discovered to control the detrimental effects of effector T cells including Th17 cells. The balance between Th17 and Treg cells influenced by interplay among transcription factors is most readily visible in the intestinal environment and is crucial for maintenance of gut immune stability. The aryl hydrocarbon receptor (AhR), best known for mediating the effects of environmental toxins, is one of the most upregulated transcription factors in Th17 cells. AhR promotes Th17 cell differentiation, and is also likely involved in Treg differentiation, thus modulating the Th17-Treg balance. AhR can be activated by environmental toxins and by natural compounds generated by bacteria normally living in the intestines. Therefore, identification of a role for AhR in Th17 biology would provide a fascinating link among environmental factors, gut microbiota, and human immunological diseases, but the precise role of AhR in infection and inflammation remains to be determined. My long-term research goal is dedicated to identifying the molecular means to modulate the balance of inflammatory and anti-inflammatory cells, thereby combating infection and preventing autoimmunity. In this proposal, we will test a new hypothesis that AhR plays a crucial role in gut immunity by influencing Th17 and Treg cell differentiation, and the differential impact on individual Th17 cytokine expression by AhR may influence IBD pathogenesis. T cell transfer model of chronic colitis, a mouse model that mimics human IBD, will be used. We will utilize loss-of-function and gain-of-function approaches to test the hypothesis by pursuing the following three specific aims: 1) Characterize AhR-deficient T cell induced colitis. 2) Determine whether attenuating Th1 or Th17 responses can ameliorate AhR-deficient T cell transfer-mediated colitis. 3) Determine the role of AhR in Treg differentiation and function in colitis pathogenesis. The knowledge gained from our proposed study will shed light on how to modulate the activity of a transcription factor to maintain the stability of the intestinal immune system and thereby prevent a variety of debilitating diseases. Since activation of AhR requires binding to certain molecules (i.e. ligands), the results of this project may allow us to identify new drug targets and develop small compounds to regulate AhR activity for therapeutic intervention in human immunological diseases. PUBLIC HEALTH RELEVANCE: The study proposed here will take the first steps toward novel insights into the action of a transcription factor, AhR, in intestinal immune equilibrium, and shed light on the role of AhR in the pathogenesis of inflammatory bowel disease. A better understanding of the role of AhR in the immune system may eventually provide novel means for treating human infectious and autoimmune diseases.