Estrogen Induced Regulation of Mucosal-Associated Invariant T Cells in Asthma

Asthma affects over 300 million people worldwide, with increasing rates annually. Males have higher asthma prevalence in adolescence, while females exhibit higher rates in adulthood. Reduced mucosal-associated invariant T (MAIT) cells are found in severe asthmatic airway disease. We hypothesize MAIT cells modulate airway inflammation and are regulated by sex hormones through their cognate hormone receptors. We compared circulating MAIT cells and ex vivo MAIT cell activation with MR-1 ligand in controls and asthmatic individuals. MAIT cells were significantly lower in asthmatic males and females compared to healthy controls. MAIT cells derived from male and female asthma patients exhibited higher levels of estrogen receptors (ERs) than those from sex-matched healthy controls, and ex vivo treatment with estrogen significantly decreased IFN-γ production in asthmatics. Estrogen treatment did not reduce IFN-γ in MAIT cells from healthy individuals. To explore the effect of estrogen on MAIT cells, we used the murine Alternaria alternata challenge model. Adoptive transfer of G-protein coupled ER (GPER-1) antagonist (G36)-treated MAIT cells into Rag1 knockout mice (Rag1^-/-) increased A. alternata-induced inflammation compared to those receiving MAIT cells without GPER-1 blockade. These findings suggest GPER-1 as a novel target to reduce airway disease in the asthmatic population.