Resolution of Allergic Airway Inflammation and Airway Hyperreactivity Is Mediated by IL-17-producing γδT Cells

Rationale gamma delta T lymphocytes are enriched within the epithelial micro-environment, where they are thought to maintain homeostasis and limit immunopathology gamma delta T cells are postulated to exert a regulatory influence during acute allergic airway disease, but the mechanism is unknown. Although regulation of allergic airway disease has been attributed to IL-17-producing T helper (Th) 17 cells, we have found that gamma delta T cells represent the major source of IL-17 in the allergic lung. Objectives: The aim of this study was to determine the contribution of these IL-17-producing gamma delta T cells to regulation of allergic airway inflammation. Methods: Flow cytometry revealed that IL-17-producing gamma delta T cells are more prevalent than IL-17(+) alpha beta T cells (Th17) in a murine model of ovalbumin-induced allergic inflammation. Measurements and Main Results: Transfer of gamma delta T cells at the peak of acute allergic responses ameliorated airway hyperresponsiveness with a corresponding acceleration in the resolution of eosinophilic and Th2-driven inflammation. Conversely, functional blockade of gamma delta T cells led to exacerbation of injury. Neither treatment changed pulmonary Th17 cell numbers. Moreover, transfer of Th17 cells had no effect on disease outcome. Importantly, IL-17-deficient gamma delta T cells were unable to promote resolution of injury. These data identify IL-17-producing gamma delta T cells as key regulators of the allergic response in vivo. Conclusions: This unfolds a new perspective for the understanding of gamma delta T cell function with regard to innate regulation of the adaptive immune responses, emphasizing that resolution of responses are important in determining the outcome of acute inflammatory episodes as well as for maintenance of tissue integrity and homeostasis.