Independent and Synergistic Effects of Interleukin-18 and Interleukin-12 in Augmenting Cytotoxic T Lymphocyte Responses and IFN-γProduction in Aging

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Abstract
Aged mice exhibit diminished CD8+ cytotoxic T lymphocyte (CTL) response to influenza virus. Previously, interleukin-12 (IL-12) was shown to partially restore in vitro influenza virus-specific CD8+ CTL activity and interferon-γ (IFN-γ) production in aged mice. The present study investigated IL-18 production and its ability to collaborate with IL-12 to enhance these responses to the levels of young mice. IL-18 protein production and mRNA expression in influenza virus-specific CTL from aged mice were higher than from young mice. In contrast, IL-18 receptor (IL-18R) mRNA expression was significantly reduced in CD8+ CTL from aged mice. Generation of CTL in the presence of IL-12 alone caused a significant increase in IFN-γ production in both old and young mice. IL-18 treatment alone significantly increased IFN-γ in CTL from young but not old mice. However, a combination of IL-18 and IL-12 significantly increased IFN-γ in both old and young mice. IL-18 and IL-12, either alone or in combination, stimulated significant influenza virus-specific cytotoxicity in both old and young mice, but no significant synergistic effect was observed. These results represent an initial demonstration of downregulated IL-18R expression in aging mice and are consistent with age-related cytotoxic T lymphocyte 1 (Tc1) deficiency. Potentially, IL-18 and IL-12 can augment IFN-γ production and reverse CD8+ CTL deficiency in aging, independently or synergistically.

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