IL-18 induces the differentiation of Th1 or Th2 cells depending upon cytokine milieu and genetic background

The functional division of CD4(+) T cells into Th1 and Th2 subsets is gener ally accepted but the mechanisms leading to their preferential induction re main elusive. Cytokines are considered the main determining factors in the initial differentiation of precursor T cells into these distinct subsets. T hus, IL-12 drives Th1 cells whereas IL-4 drives Th2 cells. Recently IL-18, originally designated as IFN-gamma -inducing factor, has been reported to s ynergize with IL-12 in the induction of Th1 cells. We report here that IL-1 8 can also induce T cells to differentiate into Th2 cells, in the presence of TCR activation, either alone or together with IL-4. This effect of IL-18 is mediated primarily on CD4(+) T cells compared with CD8(+) T cells and i s inhibited in the presence of IL-12. IL-18, however, has no effect on func tionally committed Th2 cells. Moreover, the effect of IL-18 on Th2 cell dev elopment is differentially manifest in different mouse strains, suggesting profound underlying genetic influences. BALB/c mice infected with Leishmani a major and treated with recombinant IL-18 developed exacerbated disease an d enhanced Th2 response compared with untreated controls. These data theref ore provide a novel mechanism for Th2 cell development. Thus, IL-18, a cyto kine constitutively expressed by cells of the innate response, is capable o f inducing Th2 cell differentiation in the absence of IL-4.