Article abstract
Nature Immunology 8, 967 - 974 (2007)
Published online: 20 June 2007 | Corrected online: 5 July 2007 | doi:10.1038/ni1488
IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways
Liang Zhou1, Ivaylo I Ivanov1, Rosanne Spolski2, Roy Min1,3, Kevin Shenderov1, Takeshi Egawa1, David E Levy4, Warren J Leonard2 & Dan R Littman1,3,4
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-
(TGF-). 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-, 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 ROR
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-, amplify RORt-dependent differentiation of TH-17 cells.
- The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.
- Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892, USA.
- Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA.
- Departments of Pathology and Microbiology, New York University School of Medicine, New York, New York 10016, USA.
Correspondence to: Dan R Littman1,3,4 e-mail: littman@saturn.med.nyu.edu
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