Adjuvant-dependent regulation of interleukin-17 expressing γδ T cells and inhibition of Th2 responses in allergic airways disease

Emily M Nakada, Jichuan Shan, Margaret W Kinyanjui, Elizabeth D Fixman

BackgroundTh2 immune responses are linked primarily to mild and moderate asthma, while Th17 cells, Interleukin-17A (IL-17) and neutrophilia have been implicated in more severe forms of disease. How Th2-dependent allergic reactions are influenced by Th17 and IL-17-¿¿ T cells is poorly understood. In murine models, under some conditions, IL-17 promotes Th2-biased airway inflammatory responses. However, IL-17-¿¿ T cells have been implicated in the inhibition and resolution of allergic airway inflammation and hyperresponsiveness (AHR).MethodsWe compared airway responses in Balb/c mice sensitized to OVA with (and without) a Th2-skewing aluminum-based adjuvant and the IL-17 skewing, complete Freund¿s adjuvant (CFA). AHR was measured invasively by flexiVent, while serum OVA-IgE was quantified by an enzyme immunoassay. Airway inflammatory and cytokine profiles, and cellular sources of IL-17 were assessed from bronchoalveolar lavage and/or lungs. The role of ¿¿ T cells in these responses was addressed in OVA/CFA sensitized mice using a ¿¿ T cell antibody.ResultsFollowing OVA challenge, all mice exhibited mixed eosinophilic/neutrophilic airway inflammatory profiles and elevated serum OVA-IgE. Whereas OVA/alum sensitized mice had moderate inflammation and AHR, OVA/CFA sensitized mice had significantly greater inflammation but lacked AHR. This correlated with a shift in IL-17 production from CD4+ to ¿¿ T cells. Additionally, OVA/CFA sensitized mice, given a ¿¿ TCR stimulatory antibody, showed increased frequencies of IL-17-¿¿ T cells and diminished airway reactivity and eosinophilia.ConclusionsThus, the conditions of antigen sensitization influence the profile of cells that produce IL-17, the balance of which may then modulate the airway inflammatory responses, including AHR. The possibility for IL-17-¿¿ T cells to reduce AHR and robust eosinophilic inflammation provides evidence that therapeutic approaches focused on stimulating and increasing airway IL-17-¿¿ T cells may be an effective alternative in treating steroid resistant, severe asthma.