Regulation of interleukin (IL)-18 receptor α chain expression on CD4+ T cells during T helper (Th)1/Th2 differentiation:: Critical downregulatory role of IL-4

Interleukin (IL)-18 has been well characterized as a costimulatory factor for the induction of IL-12-mediated interferon (IFN)-gamma production by T helper (Th)1 cells, but also can induce IL-4 production and thus facilitate the differentiation of Th2 cells. To determine the mechanisms by which IL-18 might regulate these diametrically distinct immune responses, we have analyzed the role of cytokines in the regulation of IL-18 receptor cc chain (IL-18R alpha) expression. The majority of peripheral CD4(+) T cells constitutively expressed the IL-18R alpha. Upon antigen stimulation in the presence of IL-12, marked enhancement of IL-18R alpha expression was observed. IL-12-mediated upregulation of IL-18R alpha required IFN-gamma. Activated CD4(+) T cells that expressed low levels of IL-18R alpha could produce IFN-gamma when stimulated with the combination of IL-12. and IL-18, while CD4(+) cells which expressed high levels of IL-18R alpha could respond to IL-18 alone. Tn contrast, T cell stimulation in the presence of IL-4 resulted in a downregulation of IL-18Ra expression. Both IL-4(-/-) and signal transducer and activator of transcription (Stat)6(-/-) T cells ex-pressed higher levels of IL-18R alpha after TCR stimulation. Furthermore, activated T cells from Stat6(-/-) mice produced more IFN-gamma in response to IL-18 than wild-type controls. Thus, positive/negative regulation of the IL-18R alpha by the major inductive cytokines (IL-12 and IL-4) determines the capacity of IL-18 to polarize an immune response.