Aryl hydrocarbon receptor regulation of T follicular helper cells

项目摘要 环境因素是免疫功能的关键调节剂。然而，免疫细胞 感知环境信号，并将它们整合到特定的免疫反应中，这一点还没有得到很好的理解。芳基 碳氢化合物受体（AHR）是环境信号调节免疫应答的一种手段。的 AHR是一种配体调节的转录因子，其结合结构上不同的分子，包括某些 污染物、饮食因素和来自微生物的化学物质。流行病学和动物研究表明， AHR结合化合物改变适应性免疫反应，但细胞成分和控制 机制尚未完全确定。CD 4 + T细胞分化和功能的变化是最重要的。 一致地观察到暴露于AHR配体的影响。我们最近发现AHR激活 改变T滤泡辅助细胞（Tfh细胞）的百分比和数量，并限制病毒特异性 感染时的抗体。这是重要的，因为Tfh细胞是体液（抗体介导的） 免疫力和环境暴露于AHR配体抑制抗体应答。然而， 调节Tfh细胞是未知的。拟议的研究将检验中心假设，即CD 4 + T细胞中的AHR 细胞影响Tfh细胞分化和功能。Tfh细胞分化涉及CD 4 + T细胞活化， 分化、增殖和存活。AHR可以单独或联合影响这些过程， Tfh细胞分化。因此，在第一个目标中，我们将使用谱系特异性Ahr基因切除，多参数 流式细胞术和酶联免疫吸附测定，以确定AHR激活是否改变Tfh细胞 在一些实施方案中，所述细胞通过影响CD 4 + T细胞活化、增殖和/或凋亡来分化。此外，这些研究将 确定Tfh细胞分化和功能的变化是否仅仅是由于AHR驱动的CD 4+细胞的变化， T细胞。第二个目标将使用单细胞RNA-seq和ChIP-seq来评估CD 4+细胞中基因的AHR调控。 编码对Tfh细胞分化至关重要的因子的T细胞。考虑到人类暴露于结合AHR的 污染物表现出更大的感染发病率和严重程度，以及减少抗体反应，以共同 这些发现将填补知识的关键空白，并为转化研究提供必要的数据， 暴露于环境中AHR结合化学品的人群。

PROJECT SUMMARY Environmental factors are key modulators of immune function. However, the mechanisms by which immune cells sense environmental cues, and integrate them into specific immune responses are not well understood. The aryl hydrocarbon receptor (AHR) is one means by which environmental signals regulate immune responses. The AHR is a ligand-regulated transcription factor that binds structurally diverse molecules, including certain pollutants, dietary factors, and chemicals from microorganisms. Epidemiological and animal studies demonstrate that AHR-binding compounds alter adaptive immune responses, but the cellular components and governing mechanisms are not fully defined. Changes to CD4+ T cell differentiation and function are among the most consistently observed effects of exposure to ligands of the AHR. We recently discovered that AHR activation alters the percentage and number of T follicular helper cells (Tfh cells) and limits the production of virus-specific antibodies during infection. This is significant because Tfh cells are required for humoral (antibody-mediated) immunity, and environmental exposure to AHR ligands dampens antibody responses. Yet, how the AHR modulates Tfh cells is not known. The proposed studies will test the central hypothesis that the AHR in CD4+ T cells affects Tfh cell differentiation and function. Tfh cell differentiation involves CD4+ T cell activation, differentiation, proliferation, and survival. The AHR could affect these processes singly or in combination to alter Tfh cell differentiation. Thus, in the first aim will we will use lineage-specific Ahr gene ablation, multi-parameter flow cytometry, and enzyme linked immunosorbent assays to determine whether AHR activation alters Tfh cell differentiation by affecting CD4+ T cell activation, proliferation, and/or apoptosis. Additionally, these studies will determine whether changes to Tfh cell differentiation and function are solely due to AHR-driven changes in CD4+ T cells. The second aim will use single cell RNA-seq and ChIP-seq to evaluate AHR regulation of genes in CD4+ T cells that encode factors critical to Tfh cell differentiation. Given that humans exposed to AHR-binding pollutants exhibit greater incidence and severity of infections, as well as reduced antibody responses to common vaccines, these findings will fill key gaps in knowledge and provide necessary data for translational studies with populations exposed to AHR binding chemicals in their environment.