Increased frequency of dual-positive TH2/TH17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma

Background: T(H)2 cells can further differentiate into dual-positive T(H)2/T(H)17 cells. The presence of dual-positive T(H)2/T(H)17 cells in the airways and their effect on asthma severity are unknown. Objective: We sought to study dual-positive T(H)2/T(H)17 cells in bronchoalveolar lavage (BAL) fluid from asthmatic patients, examine their response to glucocorticoids, and define their relevance for disease severity. Methods: Bronchoscopy and lavage were performed in 52 asthmatic patients and 25 disease control subjects. T(H)2 and T(H)2/T(H)17 cells were analyzed by using multicolor flow cytometry and confocal immunofluorescence microscopy. Cytokines were assayed by means of ELISA. Results: Dual-positive T(H)2/T(H)17 cells were present at a higher frequency in BAL fluid from asthmatic patients compared with numbers seen in disease control subjects. High-level IL-4 production was typically accompanied by high-level IL-17 production and coexpression of GATA3 and retinoic acid receptor-related orphan receptor gamma t. Increased presence of T(H)2/T(H)17 cells was associated with increased IL-17 production in lavage fluid. T(H)2/T(H)17 cell counts and IL-17 production correlated with PC20 for methacholine, eosinophil counts, and FEV1. T(H)2/T(H)17 cells, unlike T(H)2 cells, were resistant to dexamethasone-induced cell death. They expressed higher levels of mitogen-activated protein-extracellular signal-regulated kinase kinase 1, a molecule that induces glucocorticoid resistance. On the basis of the dominance of BAL fluid T(H)2 or T(H)2/T(H)17 cells, we identified 3 subgroups of asthma: T(H)2(predominant), T(H)2/T(H)17(predominant), and T(H)2/T(H)17(low). The T(H)2/T(H)17(predominant) subgroup manifested the most severe form of asthma, whereas the T(H)2/T(H)17(low) subgroup had the mildest asthma. Conclusion: Asthma is associated with a higher frequency of dual-positive T(H)2/T(H)17 cells in BAL fluid. The T(H)2/T(H)17(predominant) subgroup of asthmatic patients manifested glucocorticoid resistance in vitro. They also had the greatest airway obstruction and hyperreactivity compared with the T(H)2(predominant) and T(H)2/T(H)17(low) subgroups.