ST2effector memory helper T cells are responsible for long-term asthma exacerbation leading to female-predominant airway inflammation.

Abstract

BACKGROUND: The risk of asthma exacerbation is intrinsic to female patients. Enhanced type 2 immune responses are considered to be associated with sustained increased susceptibility to asthma exacerbation in female patients; however, the mechanisms mediating this relationship remain unclear. METHODS: Using a Dermatophagoides farinae-induced asthma mouse model, asthma-related features were evaluated. We focused on memory T cells and aimed to determine the cell types responsible for female-predominant long-term asthma exacerbations using a functional S1Preceptor antagonist and parabiotic mouse model. RESULTS: Compared to male mice, female mice demonstrated aggravated asthma exacerbation 3 months after allergen re-exposure. Higher levels of Th2 cytokines and IL-33 were observed in the lungs of female mice than in those of male mice. Moreover, enhanced Il33 mRNA synthesis in female mice was attributable to LNGFRairway epithelial cells. Increased IL-33 production or the female hormonal environment may have led to increased number of ST2CD4memory T cells. Both 17β-estradiol and progesterone were associated with the expansion of these cells; however, only 17β-estradiol maintained elevated numbers of ST2CD4memory T cells over time. The suppressed migration of ST2CD4circulating memory T cells into the lungs attenuated asthmatic inflammation in female mice to levels comparable to those observed in male mice. In contrast, ST2CD4tissue-resident memory T cells are attributable asthmatic inflammation in male mice. CONCLUSIONS: Our findings suggest that the contribution of memory T cells to asthmatic inflammation varies depending on sex, and female predominance is attributable to an increased number of ST2CD4circulating memory T cells.