Androgen Receptor Signaling Reprograms CD4+ T Cell Metabolism

Abstract

Women have higher rates of severe asthma compared to men. Severe asthma is characterized by increased Th2-mediated eosinophils and/or Th17-mediated neutrophils in the airway, leading to increased airway hyperresponsiveness and inflammation. Our prior studies showed androgens, signaling through the androgen receptor (AR), decreased Th2- and Th17-mediated airway inflammation, and increased regulatory T cell (Tregs) stability and suppressive function. However, the mechanisms by which androgens modified CD4+ T cells proliferation and effector function remained unknown. Using a mixture of in vitro and in vivo mouse models as well as primary human immune cells, we show that AR signaling reprograms specific metabolic patterns the CD4+ T cell subsets. We found that AR signaling reduces glutaminolysis in Th17 cells, reducing effector function. Additionally, MTHFD2, an enzyme in the one carbon metabolism pathway, is essential for Th2 function and may be regulated by AR. Finally, we find that AR signaling decreases glycolysis in Tregs, likely stabilizing effector function. In all, we find that AR signaling differentially regulates metabolic pathways utilized by CD4+ cells, impacting their differentiation, proliferation, and effector function with implications for sex bias in disease and effectiveness of therapeutics.