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

J Allergy Clin Immunol. 2014 Nov;134(5):1175-1186.e7. doi: 10.1016/j.jaci.2014.05.038. Epub 2014 Jul 18.


Background: TH2 cells can further differentiate into dual-positive TH2/TH17 cells. The presence of dual-positive TH2/TH17 cells in the airways and their effect on asthma severity are unknown.

Objective: We sought to study dual-positive TH2/TH17 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. TH2 and TH2/TH17 cells were analyzed by using multicolor flow cytometry and confocal immunofluorescence microscopy. Cytokines were assayed by means of ELISA.

Results: Dual-positive TH2/TH17 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 γt. Increased presence of TH2/TH17 cells was associated with increased IL-17 production in lavage fluid. TH2/TH17 cell counts and IL-17 production correlated with PC20 for methacholine, eosinophil counts, and FEV1. TH2/TH17 cells, unlike TH2 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 TH2 or TH2/TH17 cells, we identified 3 subgroups of asthma: TH2(predominant), TH2/TH17(predominant), and TH2/TH17(low). The TH2/TH17(predominant) subgroup manifested the most severe form of asthma, whereas the TH2/TH17(low) subgroup had the mildest asthma.

Conclusion: Asthma is associated with a higher frequency of dual-positive TH2/TH17 cells in BAL fluid. The TH2/TH17(predominant) subgroup of asthmatic patients manifested glucocorticoid resistance in vitro. They also had the greatest airway obstruction and hyperreactivity compared with the TH2(predominant) and TH2/TH17(low) subgroups.

Keywords: Dual-positive T(H)2/T(H)17 cells; MEK; asthma; bronchoalveolar lavage; glucocorticoid resistance.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Asthma / immunology*
  • Asthma / pathology
  • Asthma / therapy
  • Bronchoalveolar Lavage*
  • Bronchoscopy / methods
  • Dexamethasone / administration & dosage
  • Female
  • Flow Cytometry
  • GATA3 Transcription Factor
  • Glucocorticoids / administration & dosage
  • Humans
  • Interleukin-17 / immunology
  • Interleukin-4 / immunology
  • Male
  • Middle Aged
  • Severity of Illness Index
  • Th17 Cells / immunology*
  • Th17 Cells / pathology
  • Th2 Cells / immunology*
  • Th2 Cells / pathology


  • GATA3 Transcription Factor
  • GATA3 protein, human
  • Glucocorticoids
  • IL4 protein, human
  • Interleukin-17
  • Interleukin-4
  • Dexamethasone