Interleukin-21 induces the differentiation of human Tc22 cells via phosphorylation of signal transducers and activators of transcription.

Interleukin-21 (IL-21) exerts critical functions in T helper type 17 (Th17) cell development. However, the effect of IL-21 on the differentiation of IL-22-producing T cells is not clear. Here we showed that IL-21 induced the differentiation of human naive CD8(+) T cells into Tc22 cells without the expression of IL-17. The addition of transforming growth factor-β inhibited the production of IL-22 but induced the production of IL-17. Both IL-15 and IL-2 induced interferon-γ production but did not induce differentiation of Tc22, which suggests that common γ-chain signals are not specific to promote IL-22 synthesis. The IL-21 induced naive CD8(+) T cells to produce IL-22 in greater amounts than memory CD8(+) T cells. In addition, we demonstrated that IL-21 promoted the proliferation and increased the expression of IL-21 receptors on activated naive CD8(+) T cells. Furthermore, IL-21 increased the expression of granzyme B molecules. Analysis of molecular mechanisms indicated that IL-21 induced phosphorylation of signal transducers and activators of transcription 1, 3 and 5 in CD8(+) T cells. Overall, our data indicated that IL-21, an effector cytokine produced by CD4(+) T cells, might mediate the cross-talk between CD4(+) and CD8(+) T cells through the production of IL-22.