Lung dendritic cells induce TH 17 cells that produce TH 2 cytokines, express GATA-3, and promote airway inflammation

Background Dendritic cells (DCs) are crucial to shape the adaptive immune response. Extensive in vitro manipulation reprograms TH 2 and TH 17 cell lines into TH 1 cells, leading to the concept of CD4+ TH cell subset plasticity. The conversion of memory TH 17 cells into TH 2 cells or vice versa remains to be clarified. Objective We examined the localization of TH 17/TH 2 cells in vivo , their cellular origin (TH 2 vs TH 17), and the underlying mechanisms that drive the generation of these double TH producers. Methods Antigen-loaded bone marrow–derived DCs (ovalbumin-DCs) were repeatedly administered locally (intratracheally) or systemically (intravenously) to naive mice to elicit chronic airway inflammation. Inflamed lungs and mediastinal lymph nodes were examined for the presence of IL-17+ IL-13+ IL-4+ CD4+ T cells that coexpressed retinoic acid receptor–related orphan receptor γt and GATA-3 (TH 17/TH 2). Results We show that repetitive administration of inflammatory ovalbumin-DCs, locally or systemically, promoted the development of antigen-specific TH 17/TH 2 cells in lungs and mediastinal lymph nodes. Immunized mice had IgE-independent and steroid-resistant airway inflammation with a mixed neutrophil and eosinophil infiltration of the bronchoalveolar lavage fluid. Airway inflammatory signal regulatory protein α–positive DCs reprogrammed in vitro –generated TH 17 but not TH 2 cells, as well as lung effector TH cells, into TH 17/TH 2 cells. Conclusion We demonstrate the existence of TH 17/TH 2 cells that express GATA-3 in inflamed tissues and their TH 17 origin. We further propose that repeated immunization with inflammatory DCs prevails on the route of DC administration to drive TH 17/TH 2-associated chronic lung inflammation.