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

• 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
• 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

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，如哮喘，是一个日益严重的健康问题，目前没有治疗方法 解决方案对常见过敏原应答的CD 4+辅助性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患者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 哮喘患者，有和没有HDM过敏。根据我们的分析，除了典型的细胞群如TH 2， TH 17和TH 1，我们鉴定了一种新的过敏原反应性TH细胞亚群，其特征在于IFN-γ反应性T细胞亚群。 我们称之为THIFNR细胞的基因签名（Seumois等人，Science Immunology，2020）。 与过敏性个体相比，非过敏性个体中THIFNR细胞的比例显著增加。 患者，提示即使在非过敏个体中也存在过敏原特异性宿主特异性应答。而且 过敏性患者中过敏原反应性TH 2细胞的排他性存在表明其具有保护作用（抗TH 2 THIFNR细胞在暴露于过敏原的非过敏性患者中的反应）。 这种潜在的保护作用被我们的体外研究所加强，表明TNF相关的凋亡- 由THIFNR细胞产生的诱导配体（TRAIL）直接抑制由TCR触发的T细胞活化 订婚在后续的研究中，我们发现THIFNR细胞在病毒反应性TH细胞中直接针对流感病毒或流感病毒。 SARS-CoV 2，表明这些细胞在免疫反应中的作用更广泛。此外，我们发现THIFNR细胞是一种 稳定TH亚群在健康个体的大队列中。由于最近发现的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TH 2炎症发挥作用 和哮喘。 在目标1中，我们将利用干扰素刺激的反应元件（ISRE）报告小鼠和T细胞特异性 干扰素受体1（IFNAR 1）敲除小鼠，以确定THIFNR细胞在控制 哮喘模型中的过敏性气道炎症。在目标2中，我们将进行单细胞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，我们将通过使用shRNA敲低实验来测试这些TF的功能。总体而言， 该项目将提高我们对THIFNR细胞在体内如何产生以及它们如何相互作用的理解 与其他CD 4 + T细胞亚群如TH 2细胞一起减少哮喘模型中的过敏性气道炎症。