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：
10633229
负责人：
Alexander L Dent
金额：
$ 23.78万
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/10633229
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，是慢性发病的常见原因人口。哮喘也受到性别的影响，成年女性更容易受到影响比成年男性更容易患哮喘。由于目前的治疗选择，需要治疗哮喘的新策略是有限的。当昆虫抗原、动物皮屑、花粉和真菌等过敏原时，就会发生哮喘孢子进入肺部并激活过敏原特异性 CD4+ T 辅助 2 (Th2) 细胞。 Foxp3+ 调节 T (Treg) 细胞充当免疫反应的抑制剂，可以抑制炎症。然而，期间肺部 Th2 炎症，Treg 细胞抑制活性失调，Treg 细胞的一小部分发育成Th2样细胞。这种异常的 Treg 反应可以通过细胞因子 IL-33 与 Treg 细胞上表达的 ST2 受体。 ST2+ Treg 细胞保留 Foxp3 但表达增加主要 Th2 调节因子 Gata3 的作用并产生 Th2 细胞因子。 ST2+ Treg 细胞无法抑制 Th2 型炎症，还可能加剧 Th2 型炎症。最近，我们发现转录抑制因子 Bcl6 在控制 ST2+ Th2 型 Treg 细胞的发育。 Bcl6 缺陷的 Treg 细胞 ST2 和 Th2 基因增加表达水平高于野生型 Tregs，并且 Tregs 中 Bcl6 特定缺失的小鼠会发展出更严重的 Th2 型过敏性气道炎症高于野生型小鼠。我们的数据表明 Tregs 中的 IL-33/ST2 信号传导似乎也受到 Bcl6 的抑制。我们的数据表明 Bcl6 在 Treg 细胞中而不是在传统 T 细胞抑制 Th2 型炎症。因此，Bcl6 控制着一种新型 Th2 抑制 Tregs 中的通路。我们还发现 Bcl6 以性别依赖性方式调节 Tregs 中 ST2 的表达方式。与雌性野生型小鼠相比，雄性野生型小鼠的 Tregs 显示出减弱的 ST2/Th2 反应小鼠中，但来自 Bcl6 缺陷的雄性小鼠的 Tregs 显示出 ST2/Th2 反应大大增强和损失男性特异性抑制。这些发现与研究相符，表明 a) Bcl6 参与控制性别特异性基因表达；b）雄性小鼠减弱了过敏性免疫反应。在此，我们假设 Bcl6 和性激素受体调节 ST2+ Th2- 的形成像Tregs一样以相互依赖的方式，并且这种新的途径是Tregs特有的并控制着过敏性肺部炎症的严重程度。因此，在这个应用程序中，我们建议分析 ST2+ Th2 型 Tregs，重点关注 Bcl6、雄激素受体和雌激素受体的调节。这些研究将揭示新的监管途径，可用于开发新的药物哮喘疗法，并将进一步加深我们对 Bcl6 如何控制转录途径的理解由性激素介导。这些数据将为理解如何过敏性炎症疾病由 Bcl6 和性别差异控制。