title: TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice.
abstract: 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.
authors.affiliation: Department of Pediatrics, Lung Immunology and Host Defense Laboratory, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: McKinley
authors.forename: John F
authors.initials: JF
authors.lastname: Alcorn
authors.forename: Alanna
authors.initials: A
authors.lastname: Peterson
authors.forename: Rachel B
authors.initials: RB
authors.lastname: Dupont
authors.forename: Shernaaz
authors.initials: S
authors.lastname: Kapadia
authors.forename: Alison
authors.initials: A
authors.lastname: Logar
authors.forename: Adam
authors.initials: A
authors.lastname: Henry
authors.forename: Charles G
authors.initials: CG
authors.lastname: Irvin
authors.forename: Jon D
authors.initials: JD
authors.lastname: Piganelli
authors.forename: Anuradha
authors.initials: A
authors.lastname: Ray
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls