Allergen-Induced IL-6 Regulates IL-9/IL-17A Balance in CD4⁺ T cells in allergic airway inflammation

IL-9-secreting Th9 cells have been considered to play a pivotal role in the pathogenesis of atopic diseases. To what extent IL-9- producing cells are induced or regulated by sensitization with naturally occurring allergens is not yet clear. Naturally occurring allergens are capable of inducing IL-6 production in dendritic cells (DCs). Whether allergen-induced IL-6 supports a Th9 subtype by increasing IL-9 production, as observed in in vitro studies, or rather favors Th17 differentiation is not finally resolved. Therefore, in the present study we have investigated the impact of IL-6 on the Th9/Th17 balance depending on the predominant cytokine milieu and, additionally, in vivo using a DC-driven murine asthma model. In vitro, IL-6 increases Th9 cells under strong IL-4 and TGF-b activation, whereas under moderate IL-4 and TGF-b activation the presence of IL-6 shifts naive CD4⁺ cells to Th17 cells. To induce allergic airway inflammation, OVA-pulsed DCs from IL-6-deficient or wild-Type donors were adoptively transferred into BALB/c mice. Recipients receiving IL-6-producing wild-Type DCs showed a significant decrease of Th9-And IL-4-producing Th2 cells but an increase of Th17 cells in lung tissue in comparison with recipients sensitized with IL-6-deficient DCs. Our data suggest that the IL-6-mediated reduction of Th2-related IL-4 leads to a decline of the Th9 immune response and allows Th17 differentiation. The Journal of Immunology, 2016, 197: 2653-2664.