Regulation of Gut Innate Lymphoid Cells by Ahr

项目摘要/摘要： 先天淋巴样细胞(ILCs)是一类表达信号转录的新兴细胞家族 因子包括T-bet+eOMES+自然杀伤(NK)细胞、T-bet+eOMES-1型ILCs(ILC1)、GATA3+2型ILCs (ILC2)和RORgt+3型ILC(ILC3)。ILC大量存在于粘膜组织(如肺和肠道)中。 主机与环境交互的界面。ILC1、ILC2和ILC3可以很容易地对外部刺激做出反应 (微生物或饮食成分)，并产生反映其适应性免疫的效应性细胞因子 Th1、Th2和Th17/22细胞。发育的分子机制 对ILCs的功能知之甚少。芳烃受体(Ahr)是一种配体依赖的受体。 转录因子，最为人所知的是介导外来环境毒素和内源性毒素的影响 微生物和饮食代谢物。我们和其他人已经证明，AHR是ILC3维护所必需的，并且 功能。我们的初步数据揭示了AHR在ILC中的组织特异性表达和对 肠道AHR对ILC的分化和作用。我们假设AHR调节ILC2-ILC3平衡 肠道，从而影响肠道炎症和免疫力。具体地说，我们将调查1)该规定 2)AHR调节ILC2ILC3平衡的分子机制(S) 3)AHR在DSS诱导的肠道损伤中对ILCs的调节作用。这些实验将 提供了一个机会来阐明环境对肠道炎症和免疫的影响。 路径。我们的研究将为ILCs的发育和功能提供新的细胞和分子方面的见解 由AhR以组织和细胞特异性的方式调节。由于AhR是一种配体依赖的转录因子， 它的活性可以由小分子调节，调节ILC中AhR的表达和/或功能可能 代表了人类疾病治疗或预防的新范例(例如，炎症性肠病， 肠道感染和过敏性疾病)。

Project Summary/Abstract: Innate lymphoid cells (ILCs) represent an emerging family of cell types that express signature transcription factors, including T-bet+ Eomes+ natural killer (NK) cells, T-bet+ Eomes– type 1 ILCs (ILC1), Gata3+ type 2 ILCs (ILC2), and RORgt+ type 3 ILCs (ILC3). ILCs are abundantly present in mucosal tissues (e.g., lung and gut) at the interface of host-environment interactions. ILC1, ILC2, and ILC3 can readily respond to external stimuli (microbes or dietary components) and produce effector cytokines that mirror their adaptive immune counterparts, Th1, Th2, and Th17/22 cells, respectively. Molecular mechanisms underlying the development and function of ILCs are poorly understood. The aryl hydrocarbon receptor (Ahr) is a ligand-dependent transcription factor, best known to mediate the effects of xenobiotic environmental toxins and endogenous microbial and dietary metabolites. We and others have shown that Ahr is required for ILC3 maintenance and function. Our preliminary data revealed tissue-specific expression of Ahr in ILCs and differential regulation of ILC differentiation and function by Ahr in the gut. We hypothesize that Ahr regulates the ILC2-ILC3 balance in the gut, thus impacting intestinal inflammation and immunity. Specifically, we will investigate 1) the regulation of Ahr expression in ILCs, 2) the molecular mechanism(s) by which Ahr regulates the ILC2-ILC3 balance in the gut, and 3) the functional role of Ahr in regulation of ILCs in DSS-induced gut injury. These experiments will offer an opportunity to elucidate environmental impacts on gut inflammation and immunity via the Ahr-mediated pathway. Our study will provide novel cellular and molecular insights into the development and function of ILCs regulated by Ahr in a tissue- and cell-specific manner. Since Ahr is a ligand-dependent transcription factor and its activity can be regulated by small molecules, modulating Ahr expression and/or function in ILCs may represent a new paradigm for human disease treatment or prevention (e.g., inflammatory bowel disease, enteric infections, and allergic diseases).