Aryl hydrocarbon receptor regulation of T follicular helper cells

滤泡辅助 T 细胞的芳基烃受体调节

基本信息

批准号：
10480766
负责人：
Cassandra Houser
金额：
$ 1.73万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2022-09-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10480766
关键词：
AHR gene Ablation Address Adoptive Transfer Affect Animals Antibodies Antibody Response Antibody-mediated protection Antigens Apoptosis Aryl Hydrocarbon Receptor B-Lymphocytes Binding CD4 Positive T Lymphocytes Cell Differentiation process Cell physiology Cells ChIP-seq Chemicals Communication Cues DNA DNA Binding Domain Data Dendritic Cells Dietary Factors Disease Environment Environmental Exposure Environmental Risk Factor Enzyme-Linked Immunosorbent Assay Epidemiology Exhibits Experimental Designs Exposure to Flow Cytometry Foundations Gene Expression Gene Expression Regulation Gene Targeting Generations Genes Genetic Goals Health Helper-Inducer T-Lymphocyte Human Humoral Immunities Immune Immune response Immunologic Memory Immunomodulators Immunotoxicology Incidence Infection Influenza A virus Institution Knowledge Ligands Manuscripts Mediating Molecular Mus Phase Population Preparation Process Processed Genes Production Receptor Activation Receptor Signaling Regulation Regulatory T-Lymphocyte Reporting Research Scientist Severities Signal Transduction Signaling Molecule Structure of germinal center of lymph node T cell differentiation T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Testing Training Vaccines Virus adaptive immune response adaptive immunity aryl hydrocarbon receptor ligand career cell type chemical binding exposed human population fighting human pathogen immune function improved influenza infection influenzavirus method development microorganism mortality mouse model novel pollutant professor receptor binding receptor expression response single-cell RNA sequencing skills transcription factor translational study

项目摘要

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.

项目概要环境因素是免疫功能的关键调节因素。然而，免疫细胞的机制感知环境线索并将其整合到特定的免疫反应中的机制尚不清楚。芳基碳氢化合物受体（AHR）是环境信号调节免疫反应的一种手段。这 AHR 是一种配体调节的转录因子，可结合结构不同的分子，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 结合化合物会改变适应性免疫反应，但细胞成分和控制机制尚未完全定义。 CD4+ T 细胞分化和功能的变化是其中最明显的变化之一持续观察到暴露于 AHR 配体的影响。我们最近发现 AHR 激活改变滤泡辅助 T 细胞（Tfh 细胞）的百分比和数量，并限制病毒特异性的产生感染期间产生抗体。这很重要，因为 Tfh 细胞是体液（抗体介导的）免疫力和 AHR 配体的环境暴露会抑制抗体反应。然而，AHR 如何调节 Tfh 细胞尚不清楚。拟议的研究将检验 CD4+ T 中 AHR 的中心假设细胞影响 Tfh 细胞的分化和功能。 Tfh 细胞分化涉及 CD4+ T 细胞激活，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 Ahr 基因消融、多参数流式细胞术和酶联免疫吸附测定确定 AHR 激活是否改变 Tfh 细胞通过影响 CD4+ 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由 AHR 驱动的 CD4+ 变化所致 T 细胞。第二个目标将使用单细胞 RNA-seq 和 ChIP-seq 评估 CD4+ 基因的 AHR 调控 T 细胞编码对 Tfh 细胞分化至关重要的因子。鉴于人类暴露于 AHR 结合污染物表现出更高的感染发生率和严重程度，以及对常见污染物的抗体反应降低疫苗，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 结合化学物质的人群。