IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways

T helper cells that produce interleukin 17 (IL-17; 'T-H-17 cells') are a distinct subset of proinflammatory cells whose in vivo function requires IL-23 but whose in vitro differentiation requires only IL-6 and transforming growth factor-beta (TGF-beta). We demonstrate here that IL-6 induced expression of IL-21 that amplified an autocrine loop to induce more IL-21 and IL-23 receptor in naive CD4(+) T cells. Both IL-21 and IL-23, along with TGF-beta, induced IL-17 expression independently of IL-6. The effects of IL-6 and IL-21 depended on STAT3, a transcription factor required for the differentiation of T-H-17 cells in vivo. IL-21 and IL-23 induced the orphan nuclear receptor ROR gamma t, which in synergy with STAT3 promoted IL-17 expression. IL-6 therefore orchestrates a series of 'downstream' cytokine-dependent signaling pathways that, in concert with TGF-beta, amplify ROR gamma t-dependent differentiation of TH-17 cells.