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IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells

Korn T, Bettelli E, Gao W +5 more2007NatureJournal Article
10.1038/nature05970PubMed
Immune/Innate

Abstract

On activation, naive T cells differentiate into effector T-cell subsets with specific cytokine phenotypes and specialized effector functions. Recently a subset of T cells, distinct from T helper (T(H))1 and T(H)2 cells, producing interleukin (IL)-17 (T(H)17) was defined and seems to have a crucial role in mediating autoimmunity and inducing tissue inflammation. We and others have shown that transforming growth factor (TGF)-beta and IL-6 together induce the differentiation of T(H)17 cells, in which IL-6 has a pivotal function in dictating whether T cells differentiate into Foxp3+ regulatory T cells (T(reg) cells) or T(H)17 cells. Whereas TGF-beta induces Foxp3 and generates T(reg) cells, IL-6 inhibits the generation of T(reg) cells and induces the production of IL-17, suggesting a reciprocal developmental pathway for T(H)17 and T(reg) cells. Here we show that IL-6-deficient (Il6-/-) mice do not develop a T(H)17 response and their peripheral repertoire is dominated by Foxp3+ T(reg) cells. However, deletion of T(reg) cells leads to the reappearance of T(H)17 cells in Il6-/- mice, suggesting an additional pathway by which T(H)17 cells might be generated in vivo. We show that an IL-2 cytokine family member, IL-21, cooperates with TGF-beta to induce T(H)17 cells in naive Il6-/- T cells and that IL-21-receptor-deficient T cells are defective in generating a T(H)17 response.

Key Biomarkers

Foxp3IL-17IL-21IL-6T(H)17 cellsT(reg) cellsTGF-beta

Cited By (31)

  • The interleukin-17 cytokine family: critical players in host defence and inflammatory diseasesImmunology · 2011
  • IL-6: regulator of Treg/Th17 balanceEuropean Journal of Immunology · 2010
  • Th17 cytokines and their emerging roles in inflammation and autoimmunityImmunological Reviews · 2008
  • Transforming growth factor-beta: recent advances on its role in immune toleranceMethods in molecular biology · 2011
  • The dynamics of effector T cells and Foxp3+ regulatory T cells in the promotion and regulation of autoimmune encephalomyelitisJournal of Neuroimmunology · 2007
  • Characterization of Interleukin-17–Producing Regulatory T Cells in Inflamed Intestinal Mucosa From Patients With Inflammatory Bowel DiseasesGastroenterology · 2010
  • A critical function for transforming growth factor-β, interleukin 23 and proinflammatory cytokines in driving and modulating human TH-17 responses

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    • References (2)

    • Th-17 cells in the circle of immunity and autoimmunityNature Immunology · 2007
    • Transforming growth factor-beta induces development of the T (H)17 lineageNature · 2006