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

• 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
• 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

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.

哮喘是一种炎性肺疾病，是慢性发病率的常见原因 人口。哮喘也受到性的影响，使成年女性受到更频繁的影响 哮喘比成年男性。由于目前的治疗选择，需要进行哮喘治疗哮喘的新型策略 有限。当过敏原（如昆虫抗原，动物皮屑，花粉和真菌）等过敏原时，哮喘就会发展 孢子进入肺并激活过敏原特异性CD4+ T辅助辅助器2（Th2）细胞。 FOXP3+监管t （Treg）细胞充当免疫反应的抑制剂，并可以抑制炎症。但是，期间 肺中的Th2炎症，TREG细胞抑制活性被放松管制，一小部分Tregs 发展成Th2样细胞。这种变形的Treg反应可以通过细胞因子IL-33结合到与 在Treg细胞上表达的ST2受体。 ST2+ Treg细胞保留FOXP3，但表达增加 大师Th2调节剂GATA3并产生Th2细胞因子。 ST2+ Treg细胞无法抑制Th2类型 炎症，也可能加剧Th2型炎症。 最近，我们发现了转录阻遏物BCl6在控制该转录的关键作用 ST2+ Th2型Treg细胞的开发。 Bcl6缺陷型Treg细胞的ST2和Th2基因增加了 表达比野生型Tregs，而Treg中Bcl6的特异性损失的小鼠发展得更为严重 键入过敏性气道炎症，而不是野生型小鼠。我们的数据表明Treg中的IL-33/ST2信号传导 BCL6似乎也受到压制。我们的数据表明BCl6在Treg细胞中的关键作用，而不是 抑制Th2型炎症的常规T细胞。因此，Bcl6控制一种新型TH2抑制 Tregs的途径。我们还发现，Bcl6在性别依赖性中调节Treg中的ST2表达 方式。与女性相比 小鼠，但雄性BCl6缺陷小鼠的Treg显示出大大增加的ST2/TH2反应和损失 男性特异性抑制作用。这些发现与研究表明a）Bcl6参与控制 性别特异性基因表达和b）雄性小鼠已经减弱了过敏性免疫反应。 在这里，我们假设Bcl6和性激素受体调节ST2+ Th2-的形成 像Treg一样以相互依存的方式，并且这种新颖的途径是特殊的，并控制了 过敏性肺部炎症的严重程度。因此，在此应用中，我们建议分析 ST2+ Th2型Tregs，重点介绍BCl6，雄激素受体和雌激素受体的调节。 这些研究将揭示可用于开发新颖的新调节途径 哮喘的疗法，并将进一步了解BCL6如何控制转录途径 由性激素介导。这些数据将开辟新的探索途径，以了解如何 过敏性炎症性疾病由BCL6和性别差异控制。