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 journalArticle

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

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Interleukin-23
Th17 Cells
Interleukin-17
Cell Differentiation
Interleukin-6
Transforming Growth Factors
Orphan Nuclear Receptors
STAT3 Transcription Factor
Helper-Inducer T-Lymphocytes
interleukin-21
Cytokines
T-Lymphocytes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Zhou, L., Ivanov, I. I., Spolski, R., Min, R., Shenderov, K., Egawa, T., ... Littman, D. R. (2007). IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nature Immunology, 8(9), 967-974. https://doi.org/10.1038/ni1488

IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. / Zhou, Liang; Ivanov, Ivaylo I.; Spolski, Rosanne; Min, Roy; Shenderov, Kevin; Egawa, Takeshi; Levy, David E.; Leonard, Warren J.; Littman, Dan R.

In: Nature Immunology, Vol. 8, No. 9, 01.09.2007, p. 967-974.

Research output: Contribution to journalArticle

Zhou, L, Ivanov, II, Spolski, R, Min, R, Shenderov, K, Egawa, T, Levy, DE, Leonard, WJ & Littman, DR 2007, 'IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways', Nature Immunology, vol. 8, no. 9, pp. 967-974. https://doi.org/10.1038/ni1488
Zhou, Liang ; Ivanov, Ivaylo I. ; Spolski, Rosanne ; Min, Roy ; Shenderov, Kevin ; Egawa, Takeshi ; Levy, David E. ; Leonard, Warren J. ; Littman, Dan R. / IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. In: Nature Immunology. 2007 ; Vol. 8, No. 9. pp. 967-974.
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