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IL-21 and TGF-β are required for differentiation of human TH17 cells


The recent discovery of CD4+ T cells characterized by secretion of interleukin (IL)-17 (TH17 cells) and the naturally occurring regulatory FOXP3+ CD4 T cell (nTreg) has had a major impact on our understanding of immune processes not readily explained by the TH1/TH2 paradigm. TH17 and nTreg cells have been implicated in the pathogenesis of human autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis1,2. Our recent data and the work of others demonstrated that transforming growth factor-β (TGF-β) and IL-6 are responsible for the differentiation of naive mouse T cells into TH17 cells, and it has been proposed that IL-23 may have a critical role in stabilization of the TH17 phenotype3,4,5. A second pathway has been discovered in which a combination of TGF-β and IL-21 is capable of inducing differentiation of mouse TH17 cells in the absence of IL-6 (refs 6–8). However, TGF-β and IL-6 are not capable of differentiating human TH17 cells2,9 and it has been suggested that TGF-β may in fact suppress the generation of human TH17 cells10. Instead, it has been recently shown that the cytokines IL-1β, IL-6 and IL-23 are capable of driving IL-17 secretion in short-term CD4+ T cell lines isolated from human peripheral blood11, although the factors required for differentiation of naive human CD4 to TH17 cells are still unknown. Here we confirm that whereas IL-1β and IL-6 induce IL-17A secretion from human central memory CD4+ T cells, TGF-β and IL-21 uniquely promote the differentiation of human naive CD4+ T cells into TH17 cells accompanied by expression of the transcription factor RORC2. These data will allow the investigation of this new population of TH17 cells in human inflammatory disease.

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Figure 1: TGF-β and IL-21 promote T H 17 differentiation from naive CD4 + T cells.
Figure 2: TGF-β and IL-21 induce RORC2 in naive CD4 + T cells.


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We thank D. Kozoriz for assistance with flow cytometric cell sorting. Supported by grants from the NIH (D.A.H., V.K.K.), the National Multiple Sclerosis Society (D.A.H., V.K.K.), the Juvenile Diubetes Research Foundation (D.A.H., V.K.K.), and the American Cancer Society (D.E.A.). D.A.H. and V.K.K. are recipients of a Javit2 Investigator award from the NIH.

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Correspondence to David E. Anderson.

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Supplementary Methods

The file contains more detailed Supplementary Methods describing how to differentiate naïve human CD4+ T cells in the presence of TGF-β1 and IL-21. (PDF 89 kb)

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Yang, L., Anderson, D., Baecher-Allan, C. et al. IL-21 and TGF-β are required for differentiation of human TH17 cells. Nature 454, 350–352 (2008).

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