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.

与哮喘等过敏相关的疾病是一个日益严重的健康问题，目前还没有有效的治疗方法 解决办法。对常见过敏原作出反应的CD4+辅助T细胞(TH)在驱动呼吸道方面发挥着重要作用 哮喘中的炎症。 为了更好地了解T细胞亚群在过敏和哮喘中的多样性，我们分析了单个细胞 来自哮喘患者和非哮喘患者的~50,000只尘螨(HDM)变应原反应性TH细胞的转录组 哮喘患者，有无HDM过敏。从我们的分析来看，除了TH2等典型的细胞团外， Th17和TH1，我们鉴定了一种新的过敏原反应性TH细胞亚群，其特征是干扰素反应 我们称之为THIFNR细胞的基因签名(Seumois等人)。《科学免疫学》，2020)。 与过敏性相比，非过敏性个体的THIFNR细胞比例显著增加 这表明即使在非过敏性个体中也存在过敏原特异性宿主特异性反应。此外， 过敏患者中唯一的过敏原反应性TH2细胞的存在表明了保护作用(抗TH2 暴露于变应原的非过敏性患者的THIFNR细胞的反应)。 我们的体外研究表明，与肿瘤坏死因子相关的细胞凋亡-- THIFNR细胞产生的TRAIL直接抑制TCR诱导的T细胞活化 订婚。在后续研究中，我们在病毒反应性TH细胞中发现了针对流感或流感的THIFNR细胞 SARS-CoV2，这表明这些细胞在免疫反应中发挥了更广泛的作用。此外，我们还发现THIFNR细胞是一种 在一大群健康个体中稳定的TH亚群。由于最近发现了THIFNR细胞，非常 人们对它们的起源、分化、表型和功能知之甚少。我们假设这些都是 HDM反应性T细胞可能通过TRAIL参与抑制变态反应中的TH2炎症 还有哮喘。 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(IFNAR1)基因敲除小鼠确定THIFNR细胞在控制中的重要性 哮喘模型中的过敏性呼吸道炎症。在目标2中，我们将执行单细胞atac-seq分析以 确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敲除实验对这些转铁蛋白进行功能测试。总体而言，在 这个项目将提高我们对THIFNR细胞是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，以减少哮喘模型中的过敏性呼吸道炎症。