Ahr对肠道调节性T细胞作用的分子机制及其在炎症性肠病中的意义

Regulatory T cells (Tregs), a subset of CD4+ T helper cells, are characterized by the expression of nuclear transcription factor foxp3. Tregs exhibit immune regulatory functions by inhibiting autoimmune reactions and overt inflammatory responses. The intestinal microenvironment endows Treg tissue-specific properties. Thus, intestinal Tregs are distinct from periphery Tregs in terms of transcription factor expression, chemokine expression as well as cytokine production. Intestinal Tregs are crucial for preventing inflammatory bowel diseases. Aryl hydrocarbon receptor (Ahr) is a ligand-dependent transcription factor. Recent studies have shown that Ahr is expressed by Tregs and facilitates the induction of Tregs. However, the molecular mechanism of how Ahr regulates Tregs is not well understood. Furthermore, previous research focused on peripheral Tregs rather than tissue-resident Tregs. Our preliminary results showed that Ahr-deficient mice had a significant reduction of Tregs in the gut, with enhanced autoimmune responses. In addition, by using Treg conditional-knockout mice, we showed that Ahr regulated intestinal Tregs in a cell-intrinsic manner. These data suggest Ahr plays an important role in regulating Tregs in the gut. In this proposal, we aim to determine the molecular regulation of intestinal Tregs by Ahr. We will elaborate the signaling pathways involved in the regulation of intestinal Treg migration, survival, homeostasis and function by Ahr under both the steady state and inflammatory conditions. Our study will provide profound insights into building new strategies of targeting intestinal Tregs to treat inflammatory bowel diseases.

调节性T细胞（Treg）是以表达核转录因子Foxp3为特征的CD4+辅助性T细胞亚群，其功能为抑制过度的自身免疫应答和炎症反应。“肠道Treg”在转录因子、趋化因子以及细胞因子表达上与外周Treg有极大不同，展现出显著的组织特异性，抑制肠道炎症的发生及进展。芳香烃受体（Ahr）是配体依赖的核转录因子，过去的研究发现，Ahr表达于Treg中并可诱导Treg产生，但其作用的分子机制仍不明确；且过去研究皆局限于外周Treg。我们初步研究发现Ahr敲除小鼠肠道肠道Treg比例降低，伴随过高的自身免疫性应答；利用条件性基因敲除小鼠，证明Ahr对肠道Treg的调节为细胞自主性。本项目将针对Ahr调控肠道Treg分子机制的空白，密切结合肠道组织微环境，解析Ahr在稳态和肠道炎症中调节Treg迁移、存活、稳态维持及功能的分子信号通路，旨在为建立靶向“肠道Treg”治疗炎症性肠病的新策略提供科学依据。

本项目聚焦调节肠道Treg的分子机制与肠道炎症性疾病的关系，利用基因工程小鼠、细胞过继转移、肠炎模型及多组学手段，解析了芳香烃受体Ahr、TL1A/DR3信号、OX40L及表观遗传修饰酶对大肠Treg的调控作用，为肠道炎症性疾病的发病机制的阐明提供了理论基础。本项目发现Ahr可以以细胞自主性的方式调控肠道Treg的稳态维持和抑制功能，机制方面，Ahr可通过支持CD103、Gpr15等分子的表达调控Treg迁移到肠道；此外，Ahr抑制Treg表达Tbx21和Ifng，从而维持Treg的抑制功能。Ahr不影响外周以及肠道Tfr、Tfh及IgA应答。我们前期工作发现Ahr对肠道ILC3的发育和存活至关重要，因此Ahr可以通过影响多种细胞调控肠道免疫。基于以上基础，我们发现ILC3是肠道OX40Lhigh细胞的主要来源；ILC3可与Treg在肠道通过OX40L-OX40相互作用，从而支持Treg在肠道的稳态维持。此外我们发现ILC3表达死亡受体DR3，利用激动性抗体a-DR3激活其下游通路在稳态和炎症状态下都可以使得Treg大量扩增；然而DR3信号通路可通过促进ILC3分泌GM-CSF招募髓系炎症细胞浸润到肠道从而加重肠炎；以上结果证明a-DR3扩增Treg的作用无法拮抗 a-DR3引发ILC3致病性而加重肠炎的影响，该研究提出了应用a-DR3扩增Treg而治疗自身免疫性疾病的风险。我们前期工作发现Ahr可以通过影响染色体开放程度而调控Treg，我们也发现了表观遗传修饰酶对肠道Treg稳态维持和功能的调节作用；该工作发现特定的表观遗传修饰酶对Treg有组织特异性的调节作用，可特异性影响肠道Treg的功能性亚群，从而抑制肠道致炎性T细胞影响。综上所述，该项目以Ahr对肠道Treg的调节出发，解析并发现了ILC3来源的OX40L、TL1A/DR3信号通路及表观遗传修饰酶等影响肠道Treg稳态维持和功能的分子机制，以上成果有望为肠道炎症性疾病的诊断、治疗提供新靶点和新策略。