Role of a Novel Interferon Responsive T Cell Subset in Allergy and Asthma

新型干扰素反应性 T 细胞亚群在过敏和哮喘中的作用

基本信息

批准号：
10708060
负责人：
Gregory Seumois
金额：
$ 45.75万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10708060
关键词：
2019-nCoV ATAC-seq Address Adoptive Transfer Allergens Allergic Allergic Disease Allergic inflammation Allergic rhinitis Animal Model Asthma Automobile Driving Bioinformatics Blood CD4 Positive T Lymphocytes COVID-19 patient Cell Death Cell physiology Cells Characteristics Circulation Code Collaborations DNA Binding Data Development Disease Enhancers Epigenetic Process Exposure to Extrinsic asthma Follow-Up Studies Frequencies Genomics Grant Health Heterogeneity House Dust Mite Allergens Human Hypersensitivity Immune Immune response Immunology In Vitro Individual Inflammation Influenza Interferon Receptor Interferons Knockout Mice Ligands Lung Maintenance Modeling Molecular Mus Pathogenicity Patients Persons Phenotype Play Population Process Property Proteins Pyroglyphidae Reporter Response Elements Role Science Signal Transduction Structure of parenchyma of lung T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets T-cell diversity TNF-related apoptosis-inducing ligand TNFSF10 gene Testing Th2 Cells Therapeutic Tissue Sample Viral Visit Work airway inflammation allergic airway inflammation allergic response asthma model asthmatic chromatin immunoprecipitation cohort dust mite allergy experimental study flu follow-up fungus gain of function genetic signature genome-wide genomic tools improved in vivo insight knock-down loss of function mouse model novel overexpression prevent programs receptor respiratory respiratory virus response small hairpin RNA tool transcription factor transcriptome transcriptomics

项目摘要

Disease associated with allergies such as asthma are a rising health problem with no current curative solutions. CD4+ helper T cells (TH) that respond to common allergens play an important role in driving airway inflammation in asthma. To better understand the diversity of T cell subsets in allergy and asthma, we analyzed the single-cell transcriptome of ~50,000 house dust mite (HDM) allergen-reactive TH cells from asthmatics and non- asthmatics, with and without HDM allergy. From our analysis, besides canonical clusters of cells such as TH2, TH17, and TH1, we identified a novel subset of allergen-reactive TH cells characterized by an IFN responsive gene signature that we called THIFNR cells (Seumois et al. Science Immunology, 2020). Proportions of THIFNR cells were significantly increased in nonallergic individuals compared to allergic patients, suggesting an allergen-specific host specific response even in non-allergic individuals. Moreover, the exclusive presence of the allergen-reactive TH2 cells in the allergic patients suggests a protective role (anti-TH2 response) of the THIFNR cells in the non-allergic patients with exposure to allergen. This potential protective role was reinforced by our in vitro studies showing that TNF-related apoptosis- inducing ligand (TRAIL) produced by THIFNR cells directly inhibits T cell activation triggered by TCR engagement. In follow-up studies, we found THIFNR cells among viral-reactive TH cells directed towards Flu or SARS-CoV2, suggesting a broader role of those cells in immune responses. Also, we found THIFNR cells as a stable TH subset in a large cohort of healthy individuals. Because of the recent discovery of THIFNR cells, very little is known about their origins, differentiation, phenotype, and function. We hypothesize that these THIFNR HDM-reactive T cells could play a role through TRAIL engagement in dampening TH2 inflammation in allergy and asthma. In Aim 1, we will utilize Interferon-stimulated response element (ISRE) reporter mice and T cell-specific interferon receptor 1 (IFNAR1) knockout mice to determine the importance of THIFNR cells in controlling allergic airway inflammation in asthma models. In Aim 2, we will perform single-cell ATAC-seq profiling to identify transcription factors that may be involved establishing and maintaining the epigenetic state of THIFNR cells. Finally, we will test functionally those TF by using shRNA knockdown experiments. Overall, studies in this program will improve our understanding of how THIFNR cells are generated in vivo and how they interact with other CD4+ T cells subsets like TH2 cells to curtail allergic airway inflammation in asthma models.

与过敏相关的疾病（例如哮喘）是一个日益严重的健康问题，目前尚无治疗方法解决方案。对常见过敏原作出反应的 CD4+ 辅助 T 细胞 (TH) 在驱动气道中发挥重要作用哮喘中的炎症。为了更好地了解过敏和哮喘中 T 细胞亚群的多样性，我们分析了单细胞来自哮喘患者和非哮喘患者的约 50,000 个屋尘螨 (HDM) 过敏原反应性 TH 细胞的转录组患有或不患有 HDM 过敏的哮喘患者。根据我们的分析，除了 TH2 等典型细胞簇外， TH17 和 TH1，我们鉴定了一种新的过敏原反应性 TH 细胞亚群，其特征是 IFN 反应性我们将其称为 THIFNR 细胞的基因特征（Seumois 等人，《科学免疫学》，2020）。与过敏个体相比，非过敏个体中 THIFNR 细胞的比例显着增加患者，表明即使在非过敏个体中也存在过敏原特异性宿主特异性反应。此外，过敏患者中唯一存在过敏原反应性 TH2 细胞表明其具有保护作用（抗 TH2 暴露于过敏原的非过敏患者中 THIFNR 细胞的反应）。我们的体外研究证实了这种潜在的保护作用，该研究表明 TNF 相关的细胞凋亡- THIFNR细胞产生的诱导配体（TRAIL）直接抑制TCR触发的T细胞活化订婚。在后续研究中，我们发现病毒反应性 TH 细胞中的 THIFNR 细胞针对流感或 SARS-CoV2，表明这些细胞在免疫反应中发挥着更广泛的作用。此外，我们还发现 THIFNR 细胞作为在一大群健康个体中保持稳定的 TH 子集。由于最近发现了 THIFNR 细胞，关于它们的起源、分化、表型和功能知之甚少。我们假设这些 THIFNR HDM 反应性 T 细胞可以通过 TRAIL 参与抑制过敏中的 TH2 炎症和哮喘。在目标 1 中，我们将利用干扰素刺激反应元件 (ISRE) 报告小鼠和 T 细胞特异性干扰素受体 1 (IFNAR1) 敲除小鼠以确定 THIFNR 细胞在控制中的重要性哮喘模型中的过敏性气道炎症。在目标 2 中，我们将执行单细胞 ATAC-seq 分析鉴定可能参与建立和维持 THIFNR 表观遗传状态的转录因子细胞。最后，我们将通过 shRNA 敲低实验对这些 TF 进行功能测试。总体而言，研究于该计划将提高我们对 THIFNR 细胞如何在体内产生以及它们如何相互作用的理解与其他 CD4+ T 细胞亚群（如 TH2 细胞）一起减少哮喘模型中的过敏性气道炎症。