Comparative roles of IL-4, IL-13, and IL-4Rα in dendritic cell maturation and CD4⁺ Th2 cell function

IL-4 and IL-13 play key roles in Th2 immunity and asthma pathogenesis. Although the function of these cytokines is partially linked through their shared use of IL-4Rα for signaling, the interplay between these cytokines in the development of memory Th2 responses is not well delineated. In this investigation, we show that both IL-4 and IL-13 influence the maturation of dendritic cells (DC) in the lung and their ability to regulate secretion of IFN-γ and Th2 cytokines by memory CD4⁺ T cells. Cocultures of wild-type T cells with pulmonary DC from allergic, cytokine-deficient mice demonstrated that IL-4 enhanced the capacity of DC to stimulate T cell secretion of Th2 cytokines, whereas IL-13 enhanced the capacity of DC to suppress T cell secretion of IFN-γ. Because IL-4Rα is critical for IL-4 and IL-13 signaling, we also determined how variants of IL-4Rα influenced immune cell function. T cells derived from allergic mice expressing a high-affinity IL-4Rα variant produced higher levels of IL-S and IL-13 compared with T cells derived from allergic mice expressing a low-affinity IL-4Rα variant. Although DC expressing different IL-4Rα variants did not differ in their capacity to influence Th2 cytokine production, they varied in their capacity to inhibit IFN-γ production by T cells. Thus, IL-4 and IL-13 differentially-regulate DC function and the way these cells regulate T cells. The affinity of IL-4Rα also appears to be a determinant in the balance between Th2 and IFN-γ responses and thus the severity of allergic disease.