The Role of the Aryl Hydrocarbon Receptor in Intestinal Immunity

点击翻译按钮获取中文摘要

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.