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T_H17 Cells Mediate Steroid-Resistant Airway Inflammation and Airway Hyperresponsiveness in Mice¹

Laura McKinley^*, John F. Alcorn^*, Alanna Peterson^*, Rachel B. DuPont^*, Shernaaz Kapadia^*, Alison Logar^*, Adam Henry, Charles G. Irvin, Jon D. Piganelli^*, Anuradha Ray and Jay K. Kolls^2,*

^* Department of Pediatrics, Lung Immunology and Host Defense Laboratory and Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213; and Department of Medicine, Vermont Lung Center, University of Vermont, Burlington, VT 05405

Steroid-resistant asthma comprises an important source of morbidity in patient populations. T_H17 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_H17 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_H2 or T_H17 phenotype by culturing in conditioned medium. In addition, we also tested the steroid responsiveness of T_H2 and T_H17 cells. In vitro, T_H17 cytokine responses were not sensitive to dexamethasone (DEX) treatment despite immunocytochemistry confirming glucocorticoid receptor translocation to the nucleus following treatment. Transfer of T_H2 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_H17 transfer resulted in increased CXC chemokine secretion and neutrophil influx that was not attenuated by DEX. Transfer of T_H17 or T_H2 cells was sufficient to induce airway hyperresponsiveness (AHR) to methacholine. Interestingly, AHR was not attenuated by DEX in the T_H17 group. These data demonstrate that polarized Ag-specific T cells result in specific lung pathologies. Both T_H2 and T_H17 cells are able to induce AHR, whereas T_H17 cell-mediated airway inflammation and AHR are steroid resistant, indicating a potential role for T_H17 cells in steroid-resistant asthma.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Heart, Ling, and Blood Institute Grant R01HL079142 and National Institute of Allergy and Infectious Disease Grant 5T32AI060525.

² Address correspondence and reprint requests to Dr. Jay K. Kolls, Children’s Hospital of Pittsburgh, Suite 3765, 3705 Fifth Avenue, Pittsburgh, PA 15213. E-mail address: jay.kolls{at}chp.edu

³ Abbreviations used in this paper: AHR, airway hyperresponsiveness; Ad, adenovirus; BAL, bronchoalveolar lavage; DEX, dexamethasone; GR, glucocorticoid receptor; i.t., intratracheal; LH, lung homogenate; KO, knockout; rm, recombinant mouse; WT, wild type; PMN, polymorphonuclear neutrophil; PAS, periodic acid-Schiff.

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