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

Liang Zhou, Ivaylo I. Ivanov, Rosanne Spolski, Roy Min, Kevin Shenderov, Takeshi Egawa, David E. Levy, Warren J. Leonard, Dan R. Littman

Research output: Contribution to journalArticlepeer-review

1483 Scopus citations

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.

Original languageEnglish
Pages (from-to)967-974
Number of pages8
JournalNature immunology
Volume8
Issue number9
DOIs
StatePublished - Sep 1 2007
Externally publishedYes

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