The Role of the Aryl Hydrocarbon Receptor in Intestinal Immunity

描述(申请人提供)：人体免疫系统必须保持恒定的平衡才能保持健康。为了对抗有害微生物，需要提高免疫反应，但必须防止这些反应过度反应并攻击人体的正常组织。已知免疫细胞的复杂混合会影响这种平衡。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非常重要，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)。调节性T细胞(Treg)被发现可以控制包括Th17细胞在内的效应性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容易看到，对维持肠道免疫稳定至关重要。芳香烃受体(AhR)是Th17细胞中最上调的转录因子之一，以介导环境毒素的影响而闻名。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生物学中的作用将在环境因素、肠道微生物区系和人类免疫疾病之间提供有趣的联系，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确定调节炎症细胞和抗炎细胞平衡的分子手段，从而对抗感染和防止自身免疫。在这个方案中，我们将检验一个新的假设，即AhR通过影响Th17和Treg细胞的分化在肠道免疫中发挥关键作用，并且AhR对单个Th17细胞因子表达的不同影响可能影响IBD的发病。将使用慢性结肠炎的T细胞转移模型，这是一种模仿人类IBD的小鼠模型。我们将利用功能丧失和功能获得的方法来检验这一假设，以追求以下三个具体目标：1)表征AhR缺陷的T细胞引起的结肠炎。2)确定减弱Th1或Th17反应是否能改善AhR缺陷T细胞转移性结肠炎。3)确定AhR在Treg分化中的作用及在结肠炎发病机制中的作用。从我们拟议的研究中获得的知识将有助于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，从而预防各种衰弱的疾病。由于AhR的激活需要与某些分子(即配体)结合，该项目的结果可能使我们能够识别新的药物靶点并开发小分子化合物来调节AhR的活性，用于人类免疫疾病的治疗干预。 公共卫生相关性：这里提出的研究将迈出对转录因子AhR在肠道免疫平衡中的作用的新见解的第一步，并阐明AhR在炎症性肠病发病机制中的作用。更好地了解AhR在免疫系统中的作用可能最终为治疗人类感染性和自身免疫性疾病提供新的手段。

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.