TH17 Cells Mediate Steroid-Resistant Airway Inflammation and Airway Hyperresponsiveness in Mice1

Steroid-resistant asthma comprises an important source of morbidity in patient populations. T H 17 cells represent a distinct population of CD4 + Th cells that mediate neutrophilic inflammation and are characterized by the production of IL-17, IL-22, and IL-6. To investigate the function of T H 17 cells in the context of Ag-induced airway inflammation, we polarized naive CD4 + T cells from DO11.10 OVA-specific TCR-transgenic mice to a T H 2 or T H 17 phenotype by culturing in conditioned medium. In addition, we also tested the steroid responsiveness of T H 2 and T H 17 cells. In vitro, T H 17 cytokine responses were not sensitive to dexamethasone (DEX) treatment despite immunocytochemistry confirming glucocorticoid receptor translocation to the nucleus following treatment. Transfer of T H 2 cells to mice challenged with OVA protein resulted in lymphocyte and eosinophil emigration into the lung that was markedly reduced by DEX treatment, whereas T H 17 transfer resulted in increased CXC chemokine secretion and neutrophil influx that was not attenuated by DEX. Transfer of T H 17 or T H 2 cells was sufficient to induce airway hyperresponsiveness (AHR) to methacholine. Interestingly, AHR was not attenuated by DEX in the T H 17 group. These data demonstrate that polarized Ag-specific T cells result in specific lung pathologies. Both T H 2 and T H 17 cells are able to induce AHR, whereas T H 17 cell-mediated airway inflammation and AHR are steroid resistant, indicating a potential role for T H 17 cells in steroid-resistant asthma.