AhR activation in Th17 and Treg cell differentiation

描述（由申请方提供）：微生物病原体的宿主检测触发一系列事件，导致T淋巴细胞的募集和分化，其功能适合于抑制侵入性微生物。Th 17细胞是一种新定义的CD 4 + T辅助细胞亚群，分泌标志性细胞因子白细胞介素（IL）-17 A、IL-17 F和IL-22。Th 17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，失调的Th 17应答导致小鼠和人类的自身免疫。CD 4 + T细胞的另一个亚群，调节性T细胞（Tcells），抑制效应T细胞反应，并防止其潜在的致病作用。Th 17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稳态。吼？t和Foxp 3已被证明是分别指定Th 17和Treg谱系分化程序的关键转录因子。我们最近的数据表明，Th 17和Treg的命运决定可以通过ROR？t和Foxp 3，至少部分通过物理相互作用。最近，已经表明，芳烃受体（AhR），一种配体依赖性的转录因子，最为人所知的介导环境毒素（如二恶英）的影响，是一个重要的转录因子在Th 17谱系，特别是IL- 22的表达。AhR还调节Foxp 3表达，因此可能影响Th 17和Treg细胞分化的平衡。然而，很少有人知道的AhR在这些过程中的分子作用机制。本提案的目的是研究转录因子的相互作用将如何影响Th 17和Treg细胞的分化和功能。建议的实验，调查AhR，ROR？t和Foxp 3。将采用生物化学、分子和遗传学方法的组合来研究AhR在决定Th 17细胞分化程序中的分子作用、AhR和Foxp 3在Th 17和Treg分化期间的交叉调节以及AhR以配体非依赖性和细胞类型特异性方式在体内活化的功能意义。这些实验将提供一个令人兴奋的机会，提供新的机制的见解如何AhR协调与ROR？t和Foxp 3来编程Th 17和Treg细胞分化，并阐明AhR在生理稳态或微生物感染期间调节Th 17和Treg平衡的功能。更好地了解AhR调节Th 17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。

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.