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

哮喘是一种炎症性肺病，是哮喘患者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。当过敏原，如昆虫抗原，动物皮屑，花粉和真菌， 孢子进入肺并激活变应原特异性CD 4+辅助性T 2（Th 2）细胞。foxp 3+调节性T Treg细胞作为免疫反应的抑制因子，可以抑制炎症。但在 肺中的Th 2炎症，Treg细胞抑制活性失调，并且一部分Treg细胞抑制活性降低。 形成Th 2细胞。这种异常的Treg应答可以通过细胞因子IL-33结合至 ST 2受体在Treg细胞上表达。ST 2 + Treg细胞保留Foxp 3，但表达增加 Th 2调节因子Gata 3产生Th 2细胞因子。ST 2 + Treg细胞不能抑制Th 2型 炎症，也可能加剧Th 2型炎症。 最近，我们发现转录抑制因子Bcl 6在控制细胞凋亡中起关键作用。 ST 2 + Th 2型Treg细胞的发育。Bcl 6缺陷型Treg细胞具有增加的ST 2和Th 2基因 与野生型Tcl 4相比，Tcl 4中Bcl 6特异性缺失的小鼠产生更严重的Th 2 型过敏性气道炎症的小鼠比野生型小鼠。我们的数据表明，IL-33/ST 2信号转导在T细胞 也被Bcl 6抑制。我们的数据表明Bcl 6在Treg细胞中而不是在 抑制Th 2型炎症的常规T细胞。因此，Bcl 6控制一种新的Th 2抑制因子， 在Tennis的路径。我们还发现，Bcl 6以性别依赖性方式调节T细胞中ST 2的表达。 方式与雌性小鼠相比，来自雄性野生型小鼠的T细胞显示出减弱的ST 2/Th 2应答。 小鼠，但来自雄性Bcl 6缺陷小鼠的Tcl 4显示出显著增强的ST 2/Th 2应答和缺失的T细胞亚群。 男性特异性抑制这些发现与表明a）Bcl 6参与控制 性别特异性基因表达和B）雄性小鼠具有减弱的过敏性免疫应答。 在此，我们假设Bcl 6和性激素受体调节ST 2 + Th 2-T细胞的形成。 类似于TcR，以相互依赖的方式，并且这种新的途径对TcR是特异性的，并控制TcR的表达。 过敏性肺部炎症的严重程度。因此，在本申请中，我们建议分析 ST 2 + Th 2型Tcl 4，主要通过Bcl 6、雄激素受体和雌激素受体进行调节。 这些研究将揭示新的调控途径，可用于开发新的 治疗哮喘，并将进一步了解Bcl 6如何控制转录途径 由性激素调节这些数据将开辟新的探索途径，以了解如何 变应性炎性疾病由Bcl 6和性别差异控制。

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.