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

Abstract

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.

Role of IFN-γ in Th1 Differentiation: IFN-γ Regulates IL-18Rα Expression by Preventing the Negative Effects of IL-4 and by Inducing/Maintaining IL-12 Receptor β2 Expression

“…The combination of TCR ligation and IL-12 leads to significant enhancement of IL-18R␣ expression during Th1 differentiation. We and others have demonstrated that IFN-␥ itself did not directly affect IL-18R␣ expression, but that IFN-␥ was required for IL-12-driven up-regulation of IL-18R␣ expression (7,15); however, the mechanism by which IFN-␥ influenced IL-18R␣ expression and thus IL-18 responsiveness was not elucidated.…”

“…We and others (7,15) have previously shown that the ability of IL-12 to up-regulate IL-18R␣ expression is severely impaired in cultures of T cells from IFN-␥ Ϫ/Ϫ mice. Although IFN-␥ itself had no effect on IL-18R␣ expression, the combination of both IL-12 and IFN-␥ restored up-regulation of IL-18R␣.…”

Discrete Roles for Histone Acetylation in Human T Helper 1 Cell-specific Gene Expression

“…Among the defects present in Stat4 Ϫ/Ϫ mice are impaired expression of IL-18 receptors, IL-18 receptor 1, and IL-18 receptor accessory protein (IL18Rap) (21). T-bet is another transcription factor that is important for T H 1 differentiation, although it is not critical for IFN-␥ production by CD8 ϩ cells.…”

TCR-dependent sensitization of human γδ T cells to non-myeloid IL-18 in cytomegalovirus and tumor stress surveillance

“…Together, gd T cells join NK cells for their capacity to sense tissue-derived molecules alone, although their sensitivity would be more finely tuned by gd TCR engagement. Because IL12Rb2 signals through JAK2/TYK2-dependent activation of STAT4 to upregulate gene expression of IL-18Rb in ab T cells, 48 it is tempting to speculate that the gd TCR has evolved to connect to the same JAK2/TYK2 signaling pathway, thereby sensitizing gd T cells to tissue-derived soluble triggers. This putative difference between gd and ab T cells regarding the IL-18 response mechanism is intriguing and deserves further investigation.…”