Lung dendritic cells induce TH17 cells that produce TH2 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 T(H)2 and T(H)17 cell lines into T(H)1 cells, leading to the concept of CD4(+) T-H cell subset plasticity. The conversion of memory T(H)17 cells into T(H)2 cells or vice versa remains to be clarified. Objective: We examined the localization of T(H)17/T(H)2 cells in vivo, their cellular origin (T(H)2 vs T(H)17), and the underlying mechanisms that drive the generation of these double T-H 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 gamma t and GATA-3 (T(H)17/T(H)2). Results: We show that repetitive administration of inflammatory ovalbumin-DCs, locally or systemically, promoted the development of antigen-specific T(H)17/T(H)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 alpha-positive DCs reprogrammed in vitro-generated T(H)17 but not T(H)2 cells, as well as lung effector T-H cells, into T(H)17/T(H)2 cells. Conclusion: We demonstrate the existence of T(H)17/T(H)2 cells that express GATA-3 in inflamed tissues and their T(H)17 origin. We further propose that repeated immunization with inflammatory DCs prevails on the route of DC administration to drive T(H)17/T(H)2-associated chronic lung inflammation. (J Allergy Clin Immunol 2011; 128: 192-201.)