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：
10311888
负责人：
Cassandra Houser
金额：
$ 4.6万
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 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10311888
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 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.

项目摘要环境因素是免疫功能的关键调节剂。但是，免疫细胞的机制感官环境线索，并将它们整合到特定的免疫反应中。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是配体调节的转录因子，结合结构上多样的分子，包括某些分子微生物的污染物，饮食因素和化学物质。流行病学和动物研究表明 AHR结合化合物改变了自适应免疫反应，但细胞成分和管理机制尚未完全定义。 CD4+ T细胞分化和功能的变化最多一贯观察到暴露于AHR配体的影响。我们最近发现AHR激活改变T卵泡辅助细胞（TFH细胞）的百分比和数量，并限制了病毒特异性的产生感染过程中的抗体。这很重要，因为TFH细胞需要体液（抗体介导的）免疫力和对AHR配体的环境暴露会抑制抗体反应。但是，AHR怎么样调节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细胞分化和功能。 TFH细胞分化涉及CD4+ T细胞激活，分化，增殖和生存。 AHR可能会单独影响这些过程或结合起来改变 TFH细胞分化。因此，在第一个目标中，我们将使用特定谱系特异性AHR基因消融，多参数流式细胞仪和酶连接的免疫吸附测定法，以确定AHR激活是否改变TFH细胞通过影响CD4+ T细胞激活，增殖和/或凋亡来分化。此外，这些研究将确定对TFH细胞分化和功能的变化是否仅仅是由于CD4+的AHR驱动的变化 T细胞。第二个目标将使用单细胞RNA-SEQ和CHIP-SEQ评估CD4+中基因的AHR调节编码对TFH细胞分化至关重要的因子的T细胞。鉴于人类暴露于AHR结合污染物表现出更大的感染发生率和严重程度，以及对常见的抗体反应降低疫苗，这些发现将填补知识的关键空白，并为翻译研究提供必要的数据在其环境中暴露于AHR结合化学物质的种群。