Cutting edge: Steroid responsiveness in Foxp31 regulatory T cells determines steroid sensitivity during allergic airway inflammation in mice

Glucocorticoids are a highly effective first-line treatment option formany inflammatory diseases, including asthma. Some patients develop a steroidresistant condition, yet, the cellular andmolecular mechanisms underlying steroid resistance remain largely unknown. In this study, we used a murine model of steroid-resistant airway inflammation and report that combining systemic dexamethasone and intranasal IL-27 is able to reverse the inflammation. Foxp3+ regulatory T cells (Tregs) were required during dexamethasone/IL-27 treatment of steroid-resistant allergic inflammation, and importantly, direct stimulation of Tregs via glucocorticoid or IL-27 receptors was essential. Mechanistically, IL-27 stimulation in Tregs enhanced expression of the agonistic glucocorticoid receptor-a isoform. Overexpression of inhibitory glucocorticoid receptor-β isoform in Tregs alone was sufficient to elicit steroid resistance in a steroid- sensitive allergic inflammation model. Taken together, our results demonstrate for the first time, to our knowledge, that Tregs are instrumental during steroid resistance and that manipulating steroid responsiveness in Tregs may represent a novel strategy to treat steroid refractory asthma.