Aryl hydrocarbon receptor regulation of T follicular helper cells

项目总结 环境因素是免疫功能的关键调节器。然而，免疫细胞 感知环境线索，并将其整合到特定的免疫反应中，目前还没有很好的理解。芳香族 碳氢化合物受体(AHR)是环境信号调节免疫反应的途径之一。这个 AHR是一种配体调节的转录因子，它结合不同的结构分子，包括某些 污染物、饮食因素和微生物产生的化学物质。流行病学和动物研究表明 AHR结合的化合物改变了适应性免疫反应，但细胞成分和调控 机制还没有完全定义。CD4T细胞分化和功能的变化是最大的 持续观察暴露于AHR配体的影响。我们最近发现AHR的激活 改变T滤泡辅助细胞(TFH细胞)的百分比和数量，并限制病毒特异性细胞的产生 感染过程中的抗体。这一点很重要，因为TFH细胞是体液(抗体介导的)所必需的。 免疫和环境暴露于AHR配体会抑制抗体反应。然而，AHR如何 对TFH细胞的调节作用尚不清楚。拟议的研究将检验中心假设，即CD4T细胞中的AHR 细胞影响TFH细胞的分化和功能。TFH细胞分化涉及CD4T细胞的激活， 分化、增殖和存活。AHR可以单独或组合影响这些过程以改变 TFH细胞分化。因此，在第一个目标中，我们将使用谱系特异性的ahr基因消融，多参数 流式细胞术和酶联免疫吸附试验确定AHR激活是否改变TFH细胞 通过影响CD4T细胞的激活、增殖和/或凋亡而发生分化。此外，这些研究将 确定TFH细胞分化和功能的变化是否完全是由于AHR驱动的CD4变化 T细胞。第二个目标将使用单细胞rna-seq和芯片-seq来评估ahr对cd4基因的调节。 编码对TFH细胞分化至关重要的因子的T细胞。考虑到暴露于AHR结合的人类 污染物表现出更高的感染率和严重程度，以及对常见疾病的抗体反应降低。 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 暴露于环境中的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.