6). Therefore, IL-21 may achieve its effect by activating target genes downstream of STAT1, this website STAT3 and STAT5 in the activated naive CD8+ T cells. Interleukin-21 is a pleiotropic cytokine that has a broad range

of activations on immune cells. The effect of IL-21 on the differentiation of Th subsets is beginning to be delineated. In vitro stimulation of naive CD4+ T cells under Th1- or Th2-polarized conditions showed no differences in the levels of IFN-γ or IL-4 in normal and IL-21R knockout mice,15 suggesting that IL-21 has no effects on the differentiation of Th1 and Th2 cells in mice. However, IL-17 production was significantly lower in CD4+ T cells from IL-21R knockout mice than in those from normal mice under Th17-polarized conditions, demonstrating that IL-21 exerts critical functions in Th17 cell development.3,7 Two recent papers have described an IL-22-producing helper T cell population that co-expresses the chemokine receptor CCR6 and the skin-homing receptors CCR4 and CCR10.16,17 These

cells are distinct from both Th17 cells and Th1 cells. However, the effect of IL-21 on the differentiation of IL-22-producing T cells is not clear. It has been shown that IL-21 up-regulates the expression of IL-22 mRNA in activated naive CD4+ T cells.3 Consistent with these results, we found that IL-21 induced Rapamycin in vivo IL-22 production in activated naive CD4+ T cells at protein level. Unexpectedly, we demonstrated that IL-21 also induced IL-22 production in activated naive CD8+ T cells and the frequency of IL-22-producing cells in CD8+ T cells was higher than in CD4+ T cells from CBMCs. Moreover, IL-21 did

not induce IL-17 production in CD8+ T cells. These data suggest that there are some differences between the induction of IL-22 and IL-17. A transcription factor that might be involved in IL-22 expression is the aryl hydrocarbon receptor. The aryl hydrocarbon receptor agonist substantially alters the balance of IL-22 versus IL-17-producing cells.16 In line with previous studies showing that TGF-β, 3-mercaptopyruvate sulfurtransferase the critical factor in the development of Th17 cells, inhibited IL-22 production in CD4+ T cells,3 we showed that the addition of TGF-β inhibited the production of IL-22 but induced IL-17 production in activated naive CD8+ T cells. Our results demonstrated that, compared with IL-23 (data not shown), IL-21 induced higher levels of IL-22 in activated naive CD8+ T cells. Interleukin-21 belongs to the common γc-signalling cytokine family that includes IL-2, IL-7 and IL-15. Here, we found that IL-21 but not IL-15 or IL-2 induced the differentiation of Tc22 cells by naive CD8+ T cells, clearly indicating that signals mediated by the common γc are not specific to enhance IL-22 production. We found that IL-21 induced IL-22 production in naive and memory CD8+ T cells. However, naive CD8+ T cells stimulated with IL-21 produced IL-22 production in greater folds than memory CD8+ T cells.