Mononuclear phagocyte-derived IL-10 suppresses the innate IL-12/IFN-gamma axis in lung-challenged aged mice.
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.
Chiu
Bo-Chin
BC
Department of Cellular and Molecular Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Stolberg
Valerie R
VR
Chensue
Stephen W
SW
D000367:Age Factors; D000818:Animals; D003713:Dendritic Cells / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors*; D016753:Interleukin-10 / Q000276:immunology* / Q000378:metabolism; D018664:Interleukin-12 / Q000037:antagonists & inhibitors*; D007694:Killer Cells, Natural; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D008213:Lymphocyte Activation; D051379:Mice; D010586:Phagocytes / Q000378:metabolism*; D016176:T-Lymphocyte Subsets
D008070:Lipopolysaccharides; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma