IL-18, but not IL-12, is required for optimal cytokine production by influenza virus-specific CD8 ⁺ T cells

The potent innate cytokines IL-12 and IL-18 are considered to be important antigen-independent mediators of IFN-γ production by NK cells and T lymphocytes. The present analysis addresses the physiological role of IL-12 and IL-18 in the generation of virus-specific CD8 ⁺ T cells. Both wt C57BL/6J (B6) mice and mice with disrupted IL-12p40 (IL-12p40 ^{-/ -} ) or IL-18 (IL-18 ^-/- ) genes were infected with an influenza A virus and the characteristics of the resultant epitope-specific CD8 ⁺ T cell responses were compared. While IL-12 appeared to have no notable effect on either virus growth or on CD8 ⁺ T cell response profiles, the absence of IL-18 was associated with delayed virus clearance from the lung and, despite normal numbers, a significantly reduced production of IFN-γ, TNF-α, and IL-2 by epitope-specific CD8 ⁺ T cells. While this cytokine phenotype was broadly maintained in IL-12p40/lL-18 double-knockout mice, no evidence was seen for any additive effect. Together, our results suggest that IL-18, but not IL-12, induces optimal, antigen-specific production of key cytokines by CD8 ⁺ T cells for the efficient clearance of influenza virus from the lungs of infected mice.