Androgen receptor (AR) signaling limits allergen-induced airway inflammation by restricting MTHFD2 and one carbone metabolism in CD4 T cells 3735

Abstract Description Females have an increased prevalence of Th17 cell-mediated diseases, including asthma. We previously showed that androgen receptor (AR) signaling decreased Th17 differentiation and Th17-mediated airway inflammation. For maximal effector function, Th17 cells require glutamine and one carbon (1C) metabolism. Through an in vivo CRISPR screen focused on metabolic pathways, we recently found that female, but not male, Th17 cells required a 1C metabolic enzyme, methylenetetrahydrofolate dehydrogenase 2 (MTHFD2). Further, Mthfd2 expression was decreased in Th17 cells from wild-type (WT) male mice compared to WT female or ArTfm male mice, with a nonfunctional AR. Therefore, we hypothesized that AR signaling decreases MTHFD2 expression and 1C metabolism to limit Th17-mediated airway inflammation. Utilizing a model of house dust mite allergen-induced airway inflammation in male and female mice deficient in Mthfd2 in CD4 T cells, we determined that MTHFD2 expression in CD4 T cells was required for eosinophil and neutrophil infiltration into the airway and maximal lung Th2 and Th17 cells in females but not males. Additionally, we determined that lacking MTHFD2 in CD4+ T cells increased Foxp3+ Th17 cells in female mice. These data indicate that AR signaling reduces MTHFD2 expression in Th17 cells and that MTHFD2 is required for maximal allergen-induced airway inflammation. These findings provide an inflammatory mechanism for the sex-bias in asthma and other Th17-mediated diseases. Funding Sources NIH HL136664, NIH HL122554 Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)