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


On activation, naive T cells differentiate into effector T-cell subsets with specific cytokine phenotypes and specialized effector functions1. Recently a subset of T cells, distinct from T helper (TH)1 and TH2 cells, producing interleukin (IL)-17 (TH17) was defined and seems to have a crucial role in mediating autoimmunity and inducing tissue inflammation2,3,4,5. We and others have shown that transforming growth factor (TGF)-β and IL-6 together induce the differentiation of TH17 cells, in which IL-6 has a pivotal function in dictating whether T cells differentiate into Foxp3+ regulatory T cells (Treg cells) or TH17 cells6,7,8,9. Whereas TGF-β induces Foxp3 and generates Treg cells, IL-6 inhibits the generation of Treg cells and induces the production of IL-17, suggesting a reciprocal developmental pathway for TH17 and Treg cells. Here we show that IL-6-deficient (Il6-/-) mice do not develop a TH17 response and their peripheral repertoire is dominated by Foxp3+ Treg cells. However, deletion of Treg cells leads to the reappearance of TH17 cells in Il6-/- mice, suggesting an additional pathway by which TH17 cells might be generated in vivo. We show that an IL-2 cytokine family member, IL-21, cooperates with TGF-β to induce TH17 cells in naive Il6-/- T cells and that IL-21-receptor-deficient T cells are defective in generating a TH17 response.

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Figure 1: In the absence of IL-6, antigen-specific Foxp3+ Treg cells expand at the expense of effector T cells (Teff cells) in vivo.
Figure 2: Depletion of T reg cells in Il6 -/- mice restores the development of T H 17 cells and susceptibility to EAE.
Figure 3: Inhibition of induction of T reg cells and generation of T H 17 cells by IL-21.
Figure 4: IL-21-driven T H 17 differentiation is independent of IL-6.


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We thank M. Collins for providing Il21r-/- mice, and D. Kozoriz, S. Tente, R. Chandwaskar and D. Lee for cell sorting and technical assistance. This work was supported by grants from the National Multiple Sclerosis Society, the National Institutes of Health, the Juvenile Diabetes Research Foundation Center for Immunological Tolerance at Harvard, and the Deutsche Forschungsgemeinschaft. V.K.K. is the recipient of the Javits Neuroscience Investigator Award from the National Institutes of Health.

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Correspondence to Mohamed Oukka or Vijay K. Kuchroo.

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Reprints and permissions information is available at The authors declare no competing financial interests.

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Korn, T., Bettelli, E., Gao, W. et al. IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 448, 484–487 (2007).

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