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

哮喘是一种炎症性肺部疾病，是慢性疾病的常见原因。 人类人口。哮喘也受性别的影响，成年女性更容易受到影响。 比成年男性更容易患哮喘。由于目前的治疗方案，需要新的策略来治疗哮喘 是有限的。当过敏原如昆虫抗原、动物皮屑、花粉和真菌时，就会发生哮喘 孢子进入肺部，激活过敏原特异性的CD4+T辅助细胞2(Th2)细胞。Foxp3+调节性T (Treg)细胞作为免疫反应的抑制者，可以抑制炎症。然而，在 Th2炎症在肺部，Treg细胞抑制活性被解除调节，而Treg的一部分 分化为Th2样细胞。这种异常的Treg反应可以由细胞因子IL-33结合到 ST2受体在Treg细胞上表达。ST2+Treg细胞保留Foxp3，但表达增加 主控Th2调节因子GATA3并产生Th2细胞因子。ST2+Treg细胞不能抑制Th2细胞 炎症，也可能加重Th2型炎症。 最近，我们发现转录抑制因子Bcl6在控制血管紧张素转换酶的表达中起着关键作用。 ST2+Th2型Treg细胞的发育Bcl6缺陷的Treg细胞增加了ST2和Th2基因 表达比野生型Tregs，在Tregs中Bcl6特异性缺失的小鼠发生更严重的Th2 过敏性呼吸道炎症类型比野生型小鼠好。我们的数据表明IL-33/ST2信号在树突状细胞中 似乎也受到Bcl6的抑制。我们的数据表明Bcl6在Treg细胞中起着关键作用，而不是在 常规T细胞在抑制Th2型炎症中的作用因此，Bcl6控制着一种新的Th2抑制 特雷格斯的小路。我们还发现，Bcl6调节性别依赖的Tregs中ST2的表达 举止。与雌性相比，雄性野生型小鼠的Tregs表现出ST2/Th2反应减弱 小鼠，但雄性Bcl6缺陷小鼠的Tregs显示ST2/Th2反应显著增强和丢失 男性特有的抑制作用。这些发现与研究表明：a)bcl6参与控制 性别特异的基因表达；b)雄性小鼠的过敏性免疫反应减弱。 这里我们假设Bcl6和性激素受体调节ST2+Th2-的形成。 与Tregs以相互依赖的方式相似，并且这一新的途径是Tregs所特有的，并控制着 过敏性肺部炎症的严重程度。因此，在本应用程序中，我们建议分析 ST2+Th2型Tregs，主要受Bcl6、雄激素受体和雌激素受体的调节。 这些研究将揭示新的调控途径，可用于小说的发展 哮喘的治疗，并将进一步了解bcl6是如何控制转录途径的 在性激素的调节下。这些数据将开辟新的探索途径，以了解 过敏性炎症性疾病是由Bcl6和性别差异控制的。

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.