Viral infections induce CD8 T cell expansion and interferon (IFN)-γ production for defense, but the innate cytokines shaping these responses have not been identified. Although interleukin (IL)-12 has the potential to contribute, IL-12–dependent T cell IFN-γ has not been detected during viral infections. Moreover, certain viruses fail to induce IL-12, and elicit high levels of IFN-α/β to negatively regulate it. The endogenous factors promoting virus-induced T cell IFN-γ production were defined in studies evaluating CD8 T cell responses during lymphocytic choriomeningitis virus infections of mice. Two divergent supporting pathways were characterized. Under normal conditions of infections, the CD8 T cell IFN-γ response was dependent on endogenous IFN-α/β effects, but was IL-12 independent. In contrast, in the absence of IFN-α/β functions, an IL-12 response was revealed and substituted an alternative pathway to IFN-γ. IFN-α/β–mediated effects resulted in enhanced, but the alternative pathway also promoted, resistance to infection. These observations define uniquely important IFN-α/β–controlled pathways shaping T cell responses during viral infections, and demonstrate plasticity of immune responses in accessing divergent innate mechanisms to achieve similar ultimate goals.

In experimental visceral leishmaniasis, interleukin (IL)-12 initiates control over Leishmania donovani via Th1 cell activation, interferon (IFN)-gamma secretion, and granuloma formation. Because the leishmanicidal effect of conventional therapy, pentavalent antimony (Sb), also requires T cells and endogenous IFN-gamma, we tested IL-12 as a determinant of host responsiveness to chemotherapy. L. donovani-challenged IL-12p35 gene knockout (KO) mice permitted uncontrolled hepatic infection and failed to respond to Sb. In contrast, 96% of liver parasites in KO mice were killed by amphotericin B, which acts independently of immune responses. Exogenous IL-12 combined with Sb was tested in normal mice: low-dose Sb was converted from weakly to strongly leishmanicidal, and a no-effect Sb dose was converted to approximately 100% leishmanistatic. IL-12 plus Sb synergism in normal mice was IFN-gamma dependent; however, IL-12 also increased responsiveness to Sb in IFN-gamma KO mice. Thus, IL-12 regulates host IFN-gamma-dependent and -independent responses that permit and/or enhance the leishmanicidal activity of Sb.

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