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.