Prostaglandin I2 Promotes the Development of IL-17-Producing γδ T Cells That Associate with the Epithelium during Allergic Lung Inflammation

gamma delta T cells rapidly produce cytokines and represent a first line of defense against microbes and other environmental insults at mucosal tissues and are thus thought to play a local immunoregulatory role. We show that allergic airway inflammation was associated with an increase in innate IL-17-producing gamma delta T (gamma delta-17) cells that expressed the alpha E beta 7 integrin and were closely associated with the airway epithelium. Importantly, PGI(2) and its receptor IP, which downregulated airway eosinophilic inflammation, promoted the emergence of these intraepithelial gamma delta-17 cells into the airways by enhancing IL-6 production by lung eosinophils and dendritic cells. Accordingly, a pronounced reduction of gamma delta-17 cells was observed in the thymus of naive mice lacking the PGI(2) receptor IP, as well as in the lungs during allergic inflammation, implying a critical role for PGI(2) in the programming of "natural" gamma delta-17 cells. Conversely, iloprost, a stable analog of PGI(2), augmented IL-17 production by gamma delta T cells but significantly reduced airway inflammation. Together, these findings suggest that PGI(2) plays a key immunoregulatory role by promoting the development of innate intraepithelial gamma delta-17 cells through an IL-6-dependent mechanism. By enhancing gamma delta-17 cell responses, stable analogs of PGI(2) may be exploited in the development of new immunotherapeutic approaches. The Journal of Immunology, 2011, 187: 5380-5391.