A novel CD4+ T cell subset associated with allergy protection

与过敏保护相关的新型 CD4 T 细胞亚群

基本信息

批准号：
10742709
负责人：
Gregory Seumois
金额：
$ 27.45万
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：
2023
资助国家：
美国
起止时间：
2023-07-11 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10742709
关键词：
2019-nCoV Address Allergens Allergic Allergic Disease Allergic inflammation Allergic rhinitis Asthma Automobile Driving Blood specimen Brain CD4 Positive T Lymphocytes COVID-19 patient Cell Death Cell Separation Cells Circulation Clinic Coculture Techniques Code Complement Development Disease Exploratory/Developmental Grant Exposure to Extrinsic asthma Follow-Up Studies Frequencies Future Genomics Grant Health Heterogeneity House Dust Mite Allergens Human Hypersensitivity Immune Immune response Immunology In Vitro Individual Inflammation Influenza Interferon-beta Interferons Ligands Lung Mediating Pathogenicity Patients Peripheral Blood Mononuclear Cell Persons Phenotype Play Population Process Production Proliferating Property Proteins Pyroglyphidae Regulatory T-Lymphocyte Research Role Sampling Science Surface T cell receptor repertoire sequencing T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets T-cell diversity T-cell receptor repertoire TNF-related apoptosis-inducing ligand TNFSF10 gene Testing Th1 Cells Th2 Cells Therapeutic Tissue Sample Translating Viral Visit Work airway inflammation allergic response asthmatic asthmatic patient cohort cytokine dust mite allergy experimental study flu fungus genetic signature in vivo insight memory CD4 T lymphocyte novel prevent receptor respiratory respiratory virus response tool transcriptome

项目摘要

PROJECT SUMMARY 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 define the functional properties of THIFNR cells. We will perform co-culture experiments to test the ability of THIFNR cells to inhibit proliferation and function of TH2 cells in a TRAIL-dependent manner. In Aim 2 we will determine optimal conditions to induce differentiation of THIFNR cells in vitro and compare their functional properties with those generated in vivo. Finally, in Aim 3, we will determine if HDM-reactive THIFNR cells show persistence and plasticity in vivo. We will perform single-cell TCR sequencing of HDM-reactive THIFNR cells and other memory CD4+ T cell subsets isolated from longitudinally collected blood samples of HDM allergic and non-allergic subjects. By comparing TCR repertoire in longitudinal samples, we will assess persistence of THIFNR cells in vivo. Overall, functional studies in this R21 program will provide important insights into this novel CD4+ T cell subset; and form the basis of a future R01 application to conduct studies translating findings to the clinic.

项目摘要与哮喘等过敏相关的疾病是一个不断增加的健康问题，没有当前的治疗溶液。对常见过敏原反应的CD4+辅助T细胞（Th）在驱动气道炎症中起着重要作用在哮喘中。为了更好地了解过敏和哮喘中T细胞子集的多样性，我们分析了单细胞来自哮喘患者和非偶然物的约50,000家房屋粉尘螨（HDM）反应性TH细胞的转录组，有和没有HDM过敏。从我们的分析中，除了TH2，TH17和TH1等细胞的规范簇外，我们确定了以IFN响应基因特征为特征的过敏原反应性TH细胞的新型子集，我们称为ThiFNR细胞（Seumois等人，科学免疫学，2020年）。 thifnr细胞的比例为与过敏患者相比，非过敏个体的显着增加，表明过敏原特异性即使在非过敏个体中也有特定的反应。而且，过敏原反应的独家存在过敏患者中的Th2细胞表明，thifnr细胞在非 - 暴露于过敏原的过敏患者。我们的体外研究增强了这种潜在的保护作用表明THIFNR细胞产生的与TNF相关的凋亡诱导配体（TRAID）直接抑制T细胞 TCR参与触发的激活。在后续研究中，我们发现病毒反应性TH中的THIFNR细胞针对流感或SARS-COV2的细胞表明，这些细胞在免疫反应中的作用更广泛。还，我们发现，在大量健康个体中，ThiFNR细胞是稳定的TH子集。因为最近发现thifnr细胞的发现，对它们的起源，分化，表型和功能知之甚少。我们假设这些THIFNR HDM反应性T细胞可以通过缩放来通过TRAIL参与起作用 Th2过敏和哮喘中的炎症。在AIM 1中，我们将定义ThiFNR细胞的功能特性。我们将执行共培养实验进行测试 ThiFNR细胞以径向依赖性方式抑制Th2细胞的增殖和功能的能力。目标 2我们将确定最佳条件在体外诱导ThiFNR细胞的分化并比较它们具有生成体内的功能性能。最后，在AIM 3中，我们将确定HDM反应性thifnr是否细胞在体内显示持久性和可塑性。我们将对HDM反应性进行单细胞TCR测序 ThiFNR细胞和其他记忆CD4+ T细胞子集从HDM的纵向收集的血液样本中分离出来过敏和非过敏性受试者。通过比较纵向样本中的TCR曲目，我们将评估 thifnr细胞在体内的持久性。总体而言，此R21计划中的功能研究将提供重要的见解进入这个新颖的CD4+ T细胞子集；并构成了未来R01应用程序的基础，以进行翻译的研究诊所的发现。