Mononuclear phagocyte-derived IL-10 suppresses the innate IL-12/IFN-gamma axis in lung-challenged aged mice

• Published in: The Journal of immunology (1950) 2008-09, Vol.181 (5), p.3156-3166
• Main Authors: Chiu, Bo-Chin, Stolberg, Valerie R, Chensue, Stephen W
• Format: Article
• Language: English
• Subjects: Age Factors; Animals; Dendritic Cells - immunology; Inflammation - immunology; Interferon-gamma - antagonists & inhibitors; Interleukin-10 - immunology; Interleukin-10 - metabolism; Interleukin-12 - antagonists & inhibitors; Killer Cells, Natural; Lipopolysaccharides - pharmacology; Lung - drug effects; Lung - pathology; Lymphocyte Activation; Mice; Phagocytes - metabolism; T-Lymphocyte Subsets
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.181.5.3156

Previously, we reported that IL-10-producing mononuclear phagocytes increase in lungs of aged mice, causing impaired innate cytokine expression. Since dendritic cells (DCs) contribute to innate NK cell and adaptive T cell immunity, we tested the hypothesis that age-related IL-10 might influence DC function with effects on NK and T cell activation. The results showed that DC recruitment to sites of lung inflammation was normal in aged mice (>20 mo). However, IFN-gamma-producing NK cells in LPS-challenged lungs were decreased in aged as compared with young mice, which was associated with increased IL-10(+)CD11b(+)Gr-1(low)CD11c(-) cells consistent with mononuclear phagocytes. In vivo or in vitro blockade of IL-10 signaling restored IFN-gamma-producing NK cells. This restoration was reversed by IL-12 neutralization, indicating that IL-10 suppressed sources of IL-12 in aged mice. To probe DC function in adaptive immunity, we transferred young naive OVA-specific TCR transgenic T cells to old mice. Following challenge with OVA plus LPS, Ag presentation in the context of MHC-I and MHC-II occurred with similar kinetics and intensity in draining lymph nodes of young and old recipients as measured by proliferation. Despite this, aged hosts displayed impaired induction of IFN-gamma(+)CD4(+), but not IFN-gamma(+)CD8(+), effector T cells. Blockade of IL-10 signaling reversed age-associated defects. These studies indicate that the innate IL-12/IFN-gamma axis is not intrinsically defective in lungs of aged mice, but is rather suppressed by enhanced production of mononuclear phagocyte-derived IL-10. Our data identify a novel mechanism of age-associated immune deficiency.