McKinley L, Alcorn JF, Peterson A, et al. J Immunol. 2008;181(6):4089–4097
PURPOSE OF THE STUDY. To investigate the function of T-helper 17 (TH17) cells in the context of antigen-induced airway inflammation.
METHODS. The authors examined the role of TH17 cells in asthma by using a mouse model in which severe combined immunodeficient (SCID) mice were challenged with ovalbumin. On day 0, ovalbumin-specific TH2 or TH17 cells were adoptively transferred into the SCID mice. The SCID mice were challenged with ovalbumin for 3 consecutive days after cell transfer. Mice were treated with dexamethasone or phosphate-buffered saline (control) before cell transfer on day 0 and before ovalbumin challenge on day 2. In a separate experiment, wild-type mice and interleukin 17 (IL-17) receptor-null mice underwent the same protocol.
RESULTS. Transfer of ovalbumin-specific TH2 or TH17 cells into the SCID mice, followed by ovalbumin challenge, resulted in specific cellular influx into the airways and airway hyperreactivity (AHR). TH2 cell reconstitution resulted in airway inflammation that consisted mostly of eosinophils and lymphocytes and was sensitive to dexamethasone. TH17 cell reconstitution resulted in a primarily neutrophilic airway response that was resistant to dexamethasone. Adoptive transfer of ovalbumin-specific TH2 or TH17 cells, followed by ovalbumin challenge, resulted in AHR in both cases, but the AHR was sensitive to dexamethasone in the mice reconstituted with TH2 cells and not in the mice reconstituted with TH17 cells. The inflammatory and cellular responses associated with TH17 cell transfer were mediated primarily by IL-17, because IL-17 receptor-knockout mice did not develop airway neutrophilia after adoptive transfer of ovalbumin-specific TH17 cells, followed by ovalbumin challenge.
CONCLUSIONS. Reconstitution of SCID mice with TH17 cells in a model of antigen-induced airway inflammation leads to airway neutrophilia and AHR. TH17 cell-mediated neutrophil influx into the airways and AHR are resistant to dexamethasone treatment.
REVIEWERS COMMENTS. Asthma is a significant cause of morbidity and death in the pediatric population, and steroid-resistant asthma is a particularly challenging asthma phenotype to manage. This study provides insight into a possible mechanism of steroid-resistant asthma, involving neutrophil recruitment into the lung tissues by TH17 cells in an IL-17–dependent pathway. Future research should be directed at determining whether the findings in this mouse model are applicable to humans and identifying patients with this asthma phenotype. If these findings prove applicable to humans, then TH17 cell–and IL-17–specific therapies may prove useful for patients with steroid-resistant asthma.
- Copyright © 2009 by the American Academy of Pediatrics