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The differentiation of human TH-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt

Abstract

TH-17 cells are interleukin 17 (IL-17)–secreting CD4+ T helper cells involved in autoimmune disease and mucosal immunity. In naive CD4+ T cells from mice, IL-17 is expressed in response to a combination of IL-6 or IL-21 and transforming growth factor-β (TGF-β) and requires induction of the nuclear receptor RORγt. It has been suggested that the differentiation of human TH-17 cells is independent of TGF-β and thus differs fundamentally from that in mice. We show here that TGF-β, IL-1β and IL-6, IL-21 or IL-23 in serum-free conditions were necessary and sufficient to induce IL-17 expression in naive human CD4+ T cells from cord blood. TGF-β upregulated RORγt expression but simultaneously inhibited its ability to induce IL-17 expression. Inflammatory cytokines relieved this inhibition and increased RORγt-directed IL-17 expression. Other gene products detected in TH-17 cells after RORγt induction included the chemokine receptor CCR6, the IL-23 receptor, IL-17F and IL-26. Our studies identify RORγt as having a central function in the differentiation of human TH-17 cells from naive CD4+ T cells and suggest that similar cytokine pathways are involved in this process in mice and humans.

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Figure 1: RORγt is necessary and sufficient for IL-17 expression in human CD4+ T cells.
Figure 2: TGF-β induces RORγt and inhibits its activity, but this inhibition is relieved by inflammatory cytokines.
Figure 3: TGF-β, IL-1β and IL-6, IL-21 or IL-23 are required for human TH-17 polarization in serum-free conditions.
Figure 4: Induction of IL26, IL17F, IL17, RORC and IL23R mRNA during human TH-17 differentiation.
Figure 5: Expression of CCR6 and Foxp3 during human TH-17 differentiation.

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Acknowledgements

We thank the New York Cord Blood Center for providing samples; N. Taylor for suggestions; L. Zhou and I.I. Ivanov for reading the manuscript; and X. Gong, T. Jones and C. Kwak for technical assistance. Supported by the European Molecular Biology Organization (N.M.), the Irvington Institute Fellowship Program of the Cancer Research Institute (N.M.), the Howard Hughes Medical Institute (D.R.L.) and the National Institutes of Health (5 R37 AI033303 and 5 R01 AI033856 to D.R.L. and R01 AI065303 to D.U.).

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N.M., D.U. and D.R.L. designed experiments; N.M. did all experiments and N.M. and D.R.L. wrote the manuscript.

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Correspondence to Dan R Littman.

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Manel, N., Unutmaz, D. & Littman, D. The differentiation of human TH-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt. Nat Immunol 9, 641–649 (2008). https://doi.org/10.1038/ni.1610

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