An Absolute Requirement for STAT4 and a Role for IFN-γ as an Amplifying Factor in IL-12 Induction of the Functional IL-18 Receptor Complex

IL-12 and IL-18 are both proinflammatory cytokines that contribute to promoting Th1 development and IFN-γ expression. However, neither IL-12R nor IL-18R is expressed as a functional complex on most resting T cells. This study investigated the molecular mechanisms underlying the induction of an IL-18R complex in T cells. Resting T cells expressed IL-18Rα chains but did not exhibit IL-18 binding sites as detected by incubation with rIL-18 followed by anti-IL-18 Ab, suggesting a lack of IL-18Rβ expression in resting T cells. Although they also failed to express IL-12R, stimulation with anti-CD3 plus anti-CD28 generated IL-12R. Exposure of these cells to IL-12 led not only to up-regulation of IL-18Rα expression but also to induction of IL-18R binding sites on both CD4 + and CD8 + T cells concomitant with IL-18Rβ mRNA expression. The IL-18 binding site represented a functional IL-18R complex capable of exhibiting IL-18 responsiveness. IL-12 induction of an IL-18R complex and IL-18Rβ mRNA expression was not observed in STAT4-deficient (STAT4 −/− ) T cells and was substantially decreased in IFN-γ −/− T cells. However, the failure of STAT4 −/− T cells to induce an IL-18R complex was not corrected by IFN-γ. These results indicate that STAT4 and IFN-γ play an indispensable role and a role as an amplifying factor, respectively, in IL-12 induction of the functional IL-18R complex.