Comparative roles of IL-4, IL-13, and IL-4Ralpha 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-4Ralpha 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-gamma 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-gamma. Because IL-4Ralpha is critical for IL-4 and IL-13 signaling, we also determined how variants of IL-4Ralpha influenced immune cell function. T cells derived from allergic mice expressing a high-affinity IL-4Ralpha variant produced higher levels of IL-5 and IL-13 compared with T cells derived from allergic mice expressing a low-affinity IL-4Ralpha variant. Although DC expressing different IL-4Ralpha variants did not differ in their capacity to influence Th2 cytokine production, they varied in their capacity to inhibit IFN-gamma 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-4Ralpha also appears to be a determinant in the balance between Th2 and IFN-gamma responses and thus the severity of allergic disease.
Webb
Dianne C
DC
Division of Molecular Bioscience, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia. dianne.webb@anu.edu.au
Cai
Yeping
Y
Matthaei
Klaus I
KI
Foster
Paul S
PS
D000818:Animals; D001249:Asthma / Q000276:immunology*; D015704:CD4 Antigens / Q000032:analysis; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D006967:Hypersensitivity / Q000276:immunology*; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000378:metabolism; D018793:Interleukin-13 / Q000235:genetics / Q000502:physiology*; D015847:Interleukin-4 / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D011110:Polymorphism, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D018418:Th2 Cells / Q000276:immunology*; D053662:Interleukin-4 Receptor alpha Subunit
D015704:CD4 Antigens; D016207:Cytokines; D007371:Interferon-gamma; D018793:Interleukin-13; D015847:Interleukin-4; D011956:Receptors, Cell Surface; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit