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in Dendritic Cell Maturation and CD4+ Th2 Cell Function1
* Division of Molecular Bioscience, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia; and
Discipline of Immunology and Microbiology, Faculty of Health and Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia
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-4R
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-
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-. Because IL-4R is critical for IL-4 and IL-13 signaling, we also determined how variants of IL-4R influenced immune cell function. T cells derived from allergic mice expressing a high-affinity IL-4R variant produced higher levels of IL-5 and IL-13 compared with T cells derived from allergic mice expressing a low-affinity IL-4R variant. Although DC expressing different IL-4R variants did not differ in their capacity to influence Th2 cytokine production, they varied in their capacity to inhibit IFN- 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-4R also appears to be a determinant in the balance between Th2 and IFN- responses and thus the severity of allergic disease.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Health and Medical Research Peter Doherty Training Fellowship 179841 (to D.C.W.), National Health and Medical Research Council Project Grant 366765 (to D.C.W.), and National Health and Medical Research Council Program Grant 224207 (to P.S.F. and K.I.M.).
2 Address correspondence and reprint requests to Dr. Dianne C. Webb, Division of Molecular Bioscience, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia. E-mail address: dianne.webb{at}anu.edu.au
3 Abbreviations used in this paper: AHR, airways hyperreactivity; DC, dendritic cell; MHCII, MHC class II; WT, wild type; BALF, bronchoalveolar lavage fluid; MLN, mediastinal lymph node.
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