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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.

项目总结