Metabolic characteristics of Th2 and Th17 cells drive airway inflammation

Abstract

Abstract Asthma is an airway inflammatory disease that is mediated by T effector (Teff) cells, specifically Th2 and Th17 cells. Increases in disease severity leading to neutrophilic asthma is characterized by a shift towards a higher Th17 response. Typical treatment of asthmatic patients include the use of glucocoriticoid (GC) steroids. These drugs are effective at controlling inflammation in mild cases but as disease severity increases towards neutrophilic disease there is resistance by Th17 cells to the effects of these drugs. A key therapeutic objective is to identify either alternative treatments for asthma or targets that make Th17 cells more susceptible to GCs. Studies have shown that cells that have increased glycolysis and oxidative phosphorylation are more resistant to the effects of GCs. We hypothesized that the intrinsic metabolic phenotype of Th17 cells allow them to be more resistant to GCs. In this study we show, that in the murine model of airway inflammation there are differences in the expression of metabolic proteins between Th2 and Th17 cells that are present in the lung. Additionally, we show that metabolic inhibitors alter the functionality of the Teff cells and can be a target to restore sensitivity to GCs. We have also performed CyTOF analysis of asthmatic patients’ PBMCs, these data demonstrate a much higher metabolic phenotype of asthmatic patients when compared to healthy controls. Overall our studies suggest that metabolic inhibition may be a viable therapeautic in conjuction with GCs in order to dampen the function of Teffs in the airway.