Prostaglandin I₂ promotes the development of IL-17-producing γδ T cells that associate with the epithelium during allergic lung inflammation

γδ 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 γδ T (γδ-17) cells that expressed the αEβ7 integrin and were closely associated with the airway epithelium. Importantly, PGI₂ and its receptor IP, which downregulated airway eosinophilic inflammation, promoted the emergence of these intraepithelial γδ-17 cells into the airways by enhancing IL-6 production by lung eosinophils and dendritic cells. Accordingly, a pronounced reduction of γδ-17 cells was observed in the thymus of naive mice lacking the PGI₂ receptor IP, as well as in the lungs during allergic inflammation, implying a critical role for PGI₂ in the programming of "natural" γδ-17 cells. Conversely, iloprost, a stable analog of PGI₂, augmented IL-17 production by γδ T cells but significantly reduced airway inflammation. Together, these findings suggest that PGI₂ plays a key immunoregulatory role by promoting the development of innate intraepithelial γδ-17 cells through an IL-6-dependent mechanism. By enhancing γδ-17 cell responses, stable analogs of PGI₂ may be exploited in the development of new immunotherapeutic approaches.