TGF-β Enhanced IL-21-Induced Differentiation of Human IL-21-Producing CD4(+) T Cells via Smad3

IL-21 has pleiotropic effects on innate and adaptive immune response, and plays an important role in the development of autoimmune disease and antitumor activity. It has been reported that IL-21 is produced by CD4(+) T cells and NKT cells. However, the differentiation of IL-21-producing CD4(+) T cells in humans remains largely unclear. In the present study, we showed that cytokines of IL-1β, IL-6 or IL-21 induced differentiation of human IL-21-producing CD4(+) T cells, and TGF-β enhanced the effect of inflammatory cytokines on the development of IL-21-producing CD4(+) T cells. Furthermore, we found that the majority of IL-21-producing cells were distinct from Th17 cells and Th1 cells since they did not co-express IL-17 and IFN-γ. TGF-β significantly inhibited the production of IFN-γ and enhanced the effect of IL-21 on the development of IL-21-producing CD4(+) T cells. In addition, we found that IL-21 inhibited the differentiation of CD4(+) Foxp3(+) T cells induced by TGF-β. Further study indicated that IL-21 induced phosphorylation of transcriptional factors of STAT1, STAT3 and STAT5, and TGF-β induced phosphorylation of Smad3 in CD4(+) T cells. Taken together, our data indicated that TGF-β enhanced IL-21-induced differentiation of IL-21-producing CD4(+) T cells, and the majority of IL-21-producing cells were different from Th17 and Th1 cells. Our results provide a new sight regarding the differentiation of human CD4(+) T cells.