The Role of Metabolism in Th2 and Th17 Cells During Airway Inflammation
Contreras Healey, Diana Carolina
T cells play an important role in promoting inflammation in asthmatic patients and both Th2 and Th17 CD4+ T cells have been implicated in severe disease. The metabolic phenotypes and dependencies of these cells, however, have not yet been directly tested in airway inflammation. Here we establish the metabolic phenotype of T cells from asthmatic patients and a model of severe asthma characterized by Th2 and Th17 cells. Inhibitors of glucose and glutamine metabolism were also tested as potential approaches to treat airway inflammation and to augment the immunosuppressive properties of the glucocorticoid dexamethasone. Metabolic characteristics were measured by mass and flow cytometry in the lungs and T cells of asthmatic patients and mice sensitized with House Dust Mite antigen together with lipopolysaccharide that produced airway inflammation with IL-4 and IL-17 producing cells. Inhibitors of Glucose transporter 1 (Glut1) and the enzyme glutaminase (GLS) were then tested for their ability to reduce inflammation in vivo and to enhance dexamethasone cytotoxicity in vitro. T cells in asthmatic patients and mouse models were highly metabolically active, and this was most evident for IL-17-producing cells. Importantly, metabolic inhibitors reduced T cell cytokine production and eosinophilia in a model of severe asthma and augmented the immunosuppressive properties of dexamethasone. These data show that T cells are highly metabolically active in vivo in asthma and that this correlates with inflammatory cytokine production. Targeting metabolic pathways may provide a new direction to protect from disease and enhance the effectiveness of steroid therapy.