AhR activation in Th17 and Treg cell differentiation

描述(申请人提供)：宿主对微生物病原体的检测触发了一系列事件，导致具有适合抑制有害微生物的功能的T淋巴细胞的招募和分化。Th17细胞，一个新定义的CD4+T辅助细胞亚群，分泌标志性细胞因子白介素17A、白介素17F和白介素22。Th17细胞已被证明在维持粘膜完整性和免疫力方面发挥重要作用。另一方面，调节失调的Th17反应会导致小鼠和人类的自身免疫。CD4+T细胞的另一个亚群，调节性T细胞(Tregs)，抑制效应器T细胞的反应，防止其潜在的致病作用。Th17和Treg细胞之间的平衡受局部细胞因子环境的影响，并通过转录因子的协同作用来维持免疫平衡。研究表明，RoR？T和Foxp3分别是决定Th17和Treg系分化的关键转录因子。我们最近的数据表明，Th17和Treg的命运决定可以由RoR？T和Foxp3的平衡决定，至少部分是通过物理相互作用。最近的研究表明，芳香烃受体(AhR)是Th17家族中的一个重要的转录因子，尤其是对IL-22的表达。AHR还调节Foxp3的表达，从而可能影响Th17和Treg细胞分化的平衡。然而，对AhR在这些过程中的分子作用机制知之甚少。这项建议的目的是研究转录因子的相互作用如何影响Th17和Treg细胞的分化和功能。建议用实验来研究AhR、RoR？T和Foxp3之间的相互作用。我们将结合生化、分子和遗传学的方法，研究AhR在决定Th17细胞分化过程中的分子作用，AhR和Foxp3在Th17和Treg分化过程中的交叉调节，以及AhR在体内以非配体和细胞类型特异性的方式激活的功能意义。这些实验将提供一个令人兴奋的机会，为AhR如何与RoR？T和Foxp3协调来编程Th17和Treg细胞分化提供新的机制见解，并阐明AhR在生理稳定状态或微生物感染期间调节Th17和Treg平衡的功能。更好地理解AhR调节Th17和Treg细胞分化的机制将有助于识别治疗人类感染性和自身免疫性疾病的新靶点。 与公共健康相关：Th17和Treg细胞平衡在维持免疫动态平衡方面起着关键作用。这些实验将使我们能够研究AhR如何通过与ROR？T和Foxp3的协同/拮抗相互作用影响Th17和Treg细胞的分化，以及AhR在体内以细胞类型特异性的方式激活的功能。在分子水平上了解Th17和Treg细胞的分化将有助于阐明疾病的发病机制，并最终可能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): Host detection of microbial pathogens triggers a chain of events that results in recruitment and differentiation of T lymphocytes with functions suited to restrain offending microorganisms. Th17 cells, a newly defined subset of CD4+ T helper cells, secrete signature cytokines interleukin (IL)-17A, IL-17F, and IL-22. Th17 cells have been shown to play an important role in maintenance of mucosal integrity and immunity. On the other hand, dysregulated Th17 responses result in autoimmunity both in mice and in humans. Another subset of CD4+ T cells, the regulatory T cells (Tregs), suppresses effector T cell responses and prevents their potentially pathogenic effects. The balance between Th17 and Treg cells is influenced by the local cytokine milieu and is achieved through the concerted action of transcription factors to maintain immune homeostasis. ROR?t and Foxp3 have been shown to be the key transcription factors in specifying differentiation programs of Th17 and Treg lineages, respectively. Our recent data suggest that Th17 and Treg fate decision can be determined by the balance of ROR?t and Foxp3, at least in part through physical interaction. Recently, it has been shown that the aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor best known to mediate the effects of environmental toxins (e.g. dioxin), is an important transcription factor in the Th17 lineage, especially for IL- 22 expression. AhR also regulates Foxp3 expression, thus likely influencing the balance of Th17 and Treg cell differentiation. However, little is known about the molecular mechanisms of action of AhR in these processes. The objective of this proposal is to examine how the interaction of transcription factors will impact Th17 and Treg cell differentiation and function. Proposed are experiments to investigate the interplay among AhR, ROR?t, and Foxp3. A combination of biochemical, molecular, and genetic approaches will be employed to study the molecular action of AhR in determining Th17 cell differentiation program, the cross-regulation of AhR and Foxp3 during Th17 and Treg differentiation, and the functional significance of AhR activation in a ligand- independent and cell-type specific manner in vivo. These experiments will offer an exciting opportunity to provide fresh mechanistic insights into how AhR coordinates with ROR?t and Foxp3 to program Th17 and Treg cell differentiation, and shed light on AhR function in modulating Th17 and Treg balance in the physiological steady state or during microbial infection. A better understanding of the mechanism by which AhR regulates Th17 and Treg cell differentiation will be informative toward the identification of new targets for treating human infectious and autoimmune diseases. PUBLIC HEALTH RELEVANCE: The Th17 and Treg cell balance plays a critical role in maintaining immune homeostasis. The proposed experiments will allow us to investigate how AhR influences Th17 and Treg cell differentiation through cooperative/antagonistic interaction with ROR?t and Foxp3, and the function of AhR activation in vivo in a cell- type specific manner. Understanding the differentiation of Th17 and Treg cells at molecular levels will shed light on the disease pathogenesis and may eventually provide novel means for treating human infectious and autoimmune diseases.