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- Title
IL-6 programs T<sub>H</sub>-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways.
- Authors
Zhou, Liang; Ivanov, Ivaylo I; Spolski, Rosanne; Min, Roy; Shenderov, Kevin; Egawa, Takeshi; Levy, David E; Leonard, Warren J; Littman, Dan R
- Abstract
T helper cells that produce interleukin 17 (IL-17; 'TH-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-β (TGF-β). 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-β, 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 TH-17 cells in vivo. IL-21 and IL-23 induced the orphan nuclear receptor RORγt, 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-β, amplify RORγt-dependent differentiation of TH-17 cells.
- Publication
Nature Immunology, 2007, Vol 8, Issue 9, p967
- ISSN
1529-2908
- Publication type
Academic Journal
- DOI
10.1038/ni1488