IL-21 was identified by a functional screening from conditioned medium of activated T cells using Baf3-IL-21R transfectans. In normal B cells, IL-21 can mediate cell proliferation, growth arrest, and terminal differentiation, or apoptosis, depending on their activation status. IL-21 enhances B cell proliferation following incubation with an activating CD40 antibody. This result suggests that IL-21 enhances B cell function following T:B cell interactions. Nevertheless, IL-21 inhibits the proliferation of murine and human B cells stimulated with anti-IgM antibodies. In addition, IL-21 enhaces proliferation, cytotoxic activity, and IFNγ production by CD8-effector T cells, and induces terminal differentiation of activated natural killer (NK) cells. Also, IL-21 can drive Th17 responses in conjunction with TGFβ. Nevertheless, IL-21 is not essential for the differentiation of Th17 cells in vitro and in vivo, as it was showed using IL-21 and IL-21R-deficient mice. IL-6 induces the production of IL-21 from CD4 T cells upon TCR stimulation, and IL-6 and IL-21 are key players in the Tfh differentiation, characterized by increased protein expression of both Bcl6 and CXCR5. IL-21R complex is formed with the IL-21R-alpha chain and the common subunits (γc) shared with other interleukins such as IL-2, IL-4, IL-7, IL-9, and IL-15. IL-21R is wildly expressed on T cells, B cells, NK cells, and dendritic cells in all lymphoid tissues, as well as some nonimmune cells, such as fibroblasts and epithelial cells.