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Regulation of T cell-derived cytokines in allergic airway inflammation

T 细胞衍生细胞因子在过敏性气道炎症中的调节

基本信息

批准号：
10424606
负责人：
Jennifer S Chen
金额：
$ 5.18万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10424606
关键词：
3&apos Untranslated Regions Affect Affinity Allergens Allergic Disease Alternaria Antibodies Antibody Affinity Asthma B-Lymphocytes Basophils Binding Binding Sites Cell Survival Complementary DNA Data Development Disease Event Extrinsic asthma Genetic Transcription Helper-Inducer T-Lymphocyte HuR protein IgE Immune response Immunization Immunoglobulin Class Switching Immunologics Immunoprecipitation Inflammation Interleukin-4 Internal Ribosome Entry Site Length Lipopolysaccharides Maps Mediating Mediator of activation protein Messenger RNA Modeling Molecular Mus Mutate Mutation Pathogenesis Pathogenicity Patients Play Population Post-Transcriptional Regulation Prevalence Production Protein Isoforms Proteins Public Health Pulmonary Inflammation RNA-Binding Proteins Regulation Reporter Role Signal Transduction Source Structure of germinal center of lymph node Surface T cell regulation T-Lymphocyte Th2 Cells Training Transcript Translations airborne allergen allergic airway disease allergic airway inflammation anti-IgE asthma exacerbation chemical release crosslink cytokine improved insight mRNA Expression mRNA Stability mast cell microbial mouse model prevent response targeted treatment therapeutically effective

项目摘要

Project Summary The increasing prevalence of asthma over the past few decades signals an urgent need to understand disease pathogenesis and to develop more effective therapeutics. High affinity IgE plays a central role in the disease by mediating mast cell and basophil degranulation, which releases chemical mediators responsible for asthma exacerbation. T follicular helper (Tfh) cells promote the relevant high affinity antibodies for a given immune response through the cytokines they secrete. Tfh cell-derived IL-4 is required to induce high affinity IgE in response to allergens. However, IL-4 has also been considered a canonical Tfh cell cytokine, produced even during microbial immunizations that do not elicit IgE. Such studies largely rely on the use of an IL-4 cytokine reporter that indicates activation of Il4 transcription but not necessarily transcript stability or translation. Our lab has established murine models of Alternaria-induced allergic airway inflammation (AAI), which involves high affinity IgE production, as well as lipopolysaccharide (LPS)-induced lung inflammation, which does not. Using these two models, I observed Il4 mRNA expression in Tfh cells from both conditions; in contrast, I found that only Tfh cells in AAI produce IL-4 protein. My preliminary data suggest that Il4 mRNA in Tfh cells from AAI is more stable than that from LPS-induced inflammation, uncovering a post-transcriptional regulatory mechanism that governs IL-4 production in Tfh cells. My overall hypothesis is that post-transcriptional regulation of Il4 is a checkpoint dictating the high affinity IgE-promoting capacity of Tfh cells. My proposal therefore suggests a new paradigm for the regulation of IL-4 protein production in Tfh cells and the molecular basis of IgE-mediated AAI. My first aim is to identify the mRNA regulatory sequences responsible for Il4 post-transcriptional regulation in Tfh cells during AAI versus LPS-induced lung inflammation. To accomplish this, I will clone Il4 expression constructs mutated in regulatory sequences to determine the effect on Il4 mRNA stability, IL-4 protein production, and high affinity IgE responses. My second aim is to evaluate the role of an RNA-binding protein (RBP) on IL-4 production in Tfh cells during AAI. To do this, I will map RBP-Il4 binding sites, mutate these binding sites in Il4 expression constructs, and evaluate the effect of such mutations on Il4 mRNA stability, IL-4 protein production, and high affinity IgE responses. If successful, this project will define a previously undescribed mechanism of IgE regulation in asthma while also elucidating the immunologic rules that prevent the inappropriate induction of IgE in non-allergic responses. Such findings will offer valuable insight into new strategies for blocking IgE development in asthma and other allergic diseases.

项目总结