Role of Estrogen and Progesterone in Regulating Th17 T Cell Differentiation via Regulating Histone Methylation
Before puberty, the prevalence of severe asthma in girls and boys is similar. However, following puberty, women of reproductive age have an increased prevalence of severe asthma compared to men. This gender bias in severe asthma prevalence suggests that sex hormones may play a role in mediating severe asthma pathogenesis between males and females. IL-17A, a cytokine secreted by CD4+ Th17 T cells, is increased in the bronchial lavage fluid (BAL} of patients with severe asthma and is associated with an increase in airway inflammation, airway responsiveness (AR) and mucus production. The role of sex hormones in Th17 cell differentiation and IL-17A production is not fully known. Our lab has previously published that: 1) women with severe asthma have increased IL- 17A+ CD4+ memory T cells compared to men with severe asthma and 2) the ovarian hormones 17 beta-estradiol(17β-E2) and progesterone (P4) are required for maximal Th17 cell differentiation from naive CD4+ T cells and IL-17A production. We further showed that administration of exogenous 17 beta-estradiol (17β-E2) and progesterone (P4) pellets to female mice ovariectomized prior to puberty, resulting in minimal estrogen and progesterone production, increased IL-17A production from CD4+ Th17 cells differentiated ex vivo. Our results and studies of others also suggest that ovarian hormones may be regulating Th17 differentiation via epigenetic mechanisms. We hypothesize that in vivo ovarian hormones regulate H3K4me3 and H3K27me3 modifications in genes required for Th17 differentiation. We will test our hypothesis by administering slow-release vehicle or 17β-E2 plus P4 exogenous pellets into female ovariectomized mice. Three weeks after pellet implantation, we will isolate naive CD4 T cells from spleens, differentiate into Th17 cells and conduct chromatin immunoprecipitation (ChlP} assays followed by ChlP-Sequencing analysis for H3K4me3 and H3K27me3 modifications. My project will determine if 17β-E2 and P4 play an essential role in Th17 differentiation by regulating H3K4me3 and H3K27me3 modifications in naive CD4+ T cell.