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Control of ST2+ Treg Development in Allergic Disease by Bcl6 and Sex Hormone Receptors

Bcl6 和性激素受体控制过敏性疾病中 ST2 Treg 的发育

基本信息

批准号：
10535286
负责人：
Alexander L Dent
金额：
$ 19.81万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-02 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10535286
关键词：
ATAC-seq Adult Adult asthma Affect Allergens Allergic Allergic Disease Androgen Receptor Antigens Asthma Attenuated Binding Cells ChIP-seq Chromatin Structure Chronic Data Development Disease Effector Cell Estrogen Receptors FOXP3 gene Female Fungal Spores GATA3 gene Gene Expression Gene Structure Genes Genetic Transcription Gonadal Steroid Hormones Hormone Receptor Human Immune response Immunosuppressive Agents Inflammation Inflammatory Insecta Lung Mediating Morbidity - disease rate Mucous body substance Mus Pathway interactions Pollen Population Production Pulmonary Inflammation Regulation Regulatory Pathway Regulatory T-Lymphocyte Repression Role Severities Sex Differences Signal Transduction T-Lymphocyte Testing Transcription Repressor Transcriptional Regulation Wild Type Mouse Woman airway hyperresponsiveness airway inflammation allergic airway disease allergic airway inflammation allergic response animal dander cytokine deviant gene repression hormonal signals in vitro testing inflammatory lung disease insight male men novel novel strategies novel therapeutics receptor recruit response sex

项目摘要

Asthma is an inflammatory lung disease that is a common cause of chronic morbidity in the human population. Asthma is also affected by sex, such that adult women are more frequently affected by asthma than adult men. Novel strategies to treat asthma are needed since current treatment options are limited. Asthma develops when allergens such as insect antigens, animal dander, pollen and fungal spores enter the lung and activate allergen-specific CD4+ T helper 2 (Th2) cells. Foxp3+ regulatory T (Treg) cells act as suppressors of the immune response and can inhibit inflammation. However, during Th2 inflammation in the lung, Treg cell suppressive activity is deregulated and a fraction of Tregs develop into Th2-like cells. This deviant Treg response can be promoted by the cytokine IL-33 binding to the ST2 receptor expressed on Treg cells. ST2+ Treg cells retain Foxp3 but have increased expression of the master Th2 regulator Gata3 and produce Th2 cytokines. ST2+ Treg cells fail to suppress Th2 type inflammation and may also exacerbate Th2 type inflammation. Recently, we have found a key role for the transcriptional repressor Bcl6 in controlling the development of ST2+ Th2-type Treg cells. Bcl6-deficient Treg cells have increased ST2 and Th2 gene expression than wild-type Tregs, and mice with a specific loss of Bcl6 in Tregs develop more severe Th2 type allergic airway inflammation than wild-type mice. Our data indicate that IL-33/ST2 signaling in Tregs also appears to be repressed by Bcl6. Our data indicate a critical role for Bcl6 in Treg cells rather than in conventional T cells in repressing Th2 type inflammation. Thus, Bcl6 controls a novel Th2 inhibitory pathway in Tregs. We have also found that Bcl6 regulates ST2 expression in Tregs in a sex-dependent manner. Tregs from male wild-type mice show a dampened ST2/Th2 response compared to female mice, but Tregs from male Bcl6-deficient mice show a greatly augmented ST2/Th2 response and a loss of male-specific inhibition. These findings fit with studies showing that a) Bcl6 is involved in controlling sex-specific gene expression and b) that male mice have attenuated allergic immune responses. Here we hypothesize that Bcl6 and sex hormone receptors regulate the formation of ST2+ Th2- like Tregs in an inter-dependent manner, and that this novel pathway is specific to Tregs and controls the severity of allergic lung inflammation. Thus in this application we propose to analyze the development of ST2+ Th2-type Tregs, focusing on regulation by Bcl6, the androgen receptor and the estrogen receptor. These studies will reveal novel regulatory pathways that can be exploited for the development of novel therapies for asthma, and will further our understanding of how Bcl6 controls transcriptional pathways mediated by sex hormones. These data will open up new avenues of exploration for understanding how allergic inflammatory disease is controlled by Bcl6 and by sex differences.

哮喘是一种炎症性肺部疾病，是美国慢性疾病的常见原因