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Two key events occur during the differentiation of IFN-γ-secreting Th1 cells: up-regulation of IL-12Rβ2 and IL-12-driven up-regulation of IL-18Rα. We previously demonstrated that IL-12-driven up-regulation of IL-18Rα expression is severely impaired in IFN-γ−/− mice. However, it was unclear from these studies how IFN-γ influenced IL-18Rα since IFN-γ alone had no direct effect on IL-18Rα expression. In the absence of IL-4, IL-12-dependent up-regulation of IL-18Rα/IL-12Rβ2 was independent of IFN-γ. However, in the presence of IL-4, IFN-γ functions to limit the negative effects of IL-4 on both IL-18Rα and IL-12Rβ2. Neutralization of IL-4 restored IL-12-driven up-regulation of IL-18Rα/IL-12Rβ2 in an IFN-γ-independent fashion. In the absence of both IL-12 and IL-4, IFN-γ up-regulates IL-12β2 expression and primes IFN-γ-producing Th1 cells. When T cells were primed in the presence of IL-4, no correlation was found between the levels of expression of the IL-18Rα or the IL-12Rβ2 and the capacity of these cells to produce IFN-γ, suggesting that IL-4 may also negatively affect IL-12-mediated signal transduction and thus Th1 differentiation. These data clarify the role of IFN-γ in regulation of IL-18Rα/IL-12Rβ2 during both IL-12-dependent and IL-12-independent Th1 differentiation.

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