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，目前尚无治疗方法