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Induction and molecular signature of pathogenic TH17 cells

Abstract

Interleukin 17 (IL-17)-producing helper T cells (TH17 cells) are often present at the sites of tissue inflammation in autoimmune diseases, which has led to the conclusion that TH17 cells are main drivers of autoimmune tissue injury. However, not all TH17 cells are pathogenic; in fact, TH17 cells generated with transforming growth factor-β1 (TGF-β1) and IL-6 produce IL-17 but do not readily induce autoimmune disease without further exposure to IL-23. Here we found that the production of TGF-β3 by developing TH17 cells was dependent on IL-23, which together with IL-6 induced very pathogenic TH17 cells. Moreover, TGF-β3-induced TH17 cells were functionally and molecularly distinct from TGF-β1-induced TH17 cells and had a molecular signature that defined pathogenic effector TH17 cells in autoimmune disease.

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Figure 1: The induction of TGF-β3 in TH17 cells.
Figure 2: TGF-β3-induced TH17 cells are very pathogenic in inducing autoimmunity.
Figure 3: The pathogenicity of TH17 cells induced with TGF-β3 and IL-6 is very similar to that of TH17 cells induced with IL-1β, IL-6 and IL-23.
Figure 4: Identification of transcriptional signature for pathogenic TH17 cells.
Figure 5: Exogenous TGF-β3 can overcome the absence of T-bet.

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Acknowledgements

We thank R. Bomireddy (University of Arizona) for mice with loxP-flanked Tgfb3 alleles; and D. Kozoriz for cell sorting. Supported by the US National Institutes of Health (NS030843, NS045937, AI073748 and AI045757 to V.K.K.; AI075285 and AI093903 to F.J.Q.; 1P01HG005062-01 and DP1-OD003958-01 to A.R.; and K01DK090105 to S.X.), the National Multiple Sclerosis Society (RG2571; RG4111A1 to F.J.Q.), the Crohn's and Colitis Foundation of America (A.A.), the Merkin Foundation for Stem Cell Research at the Broad Institute, the National Human Genome Research Institute and the Howard Hughes Medical Institute.

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Y.L. and A.A. designed the study, did experiments, analyzed data and wrote the manuscript; A.P., S.X., S.K., M.K. and C.W. did in vitro experiments; N.Y., F.J.Q. and A.R. did the bioinformatics analysis of gene-expression data; R.A.S. did the immunohistochemical analysis; D.A.H. provided discussions; and V.K.K. and A.A. supervised the study and edited the manuscript.

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Correspondence to Amit Awasthi or Vijay K Kuchroo.

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Lee, Y., Awasthi, A., Yosef, N. et al. Induction and molecular signature of pathogenic TH17 cells. Nat Immunol 13, 991–999 (2012). https://doi.org/10.1038/ni.2416

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