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Generation of pathogenic TH17 cells in the absence of TGF-β signalling

Nature volume 467, pages 967–971 (2010)Cite this article

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Abstract

CD4+ T-helper cells that selectively produce interleukin (IL)-17 (TH17), are critical for host defence and autoimmunity1,2,3,4. Although crucial for TH17 cells in vivo5,6, IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been proposed to be the factors responsible for initiating specification7,8,9,10. Here we show that TH17 differentiation can occur in the absence of TGF-β signalling. Neither IL-6 nor IL-23 alone efficiently generated TH17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naive precursors, independently of TGF-β. Epigenetic modification of the Il17a, Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed RORγt (encoded by Rorc) and T-bet. T-bet+RORγt+ TH17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred TH17 cells generated with IL-23 without TGF-β1 were pathogenic in this disease model. These data indicate an alternative mode for TH17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore may have therapeutic implications.

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Figure 1: In vivo and in vitro differentiation of T H 17 cells in the absence of TGF-β signalling.
Figure 2: IL-23 upregulates IL-23R and modifies the Il17 and Rorc loci in the absence of TGF-β.
Figure 3: IL-23-induced T H 17 cells express T-bet but not IL-9 and IL-10.
Figure 4: RORγt + T-bet + T H 17 cells arise during CNS inflammation, and T-bet-expressing, IL-23-induced T H 17 cells are more pathogenic.

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Gene Expression Omnibus

Data deposits

The ChIP-seq and microarray data sets are deposited in Gene Expression Omnibus database under accession numbers GSE23505 and GSE23681.

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Acknowledgements

We thank J. Simone, J. Lay (Flow Cytometry Section, NIAMS) and the NIAMS LACU staff for technical support. This work has been supported by the Intramural Research Programs of NIAMS, NIDCR and NIAID.

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Author notes

  1. Arian Laurence and Xiang-Ping Yang: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Kamran Ghoreschi, Arian Laurence, Xiang-Ping Yang, Haydeé L. Ramos, Lai Wei, Yuka Kanno, Wendy T. Watford & John J. O’Shea

  2. Merck Research Laboratories, Palo Alto, 94304, California, USA

    Cristina M. Tato, Mandy J. McGeachy & Daniel J. Cua

  3. Mucosal Immunology Unit, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Joanne E. Konkel & WanJun Chen

  4. Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Todd S. Davidson, Qian Chen & Ethan M. Shevach

  5. Mucosal Immunology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Nicolas Bouladoux, John R. Grainger & Yasmine Belkaid

  6. Biodata Mining and Discovery Section, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Hong-Wei Sun

  7. Institut Pasteur, Lymphoid Tissue Development Unit, Paris, 75724, France

    Gérard Eberl

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Contributions

K.G. designed, performed, analysed and interpreted all the experiments and wrote the manuscript. A.L., X.-P.Y., M.J.G. and C.M.T. planned and performed experiments and helped to write the manuscript; L.W. and H.-W.S. interpreted the microarray experiments and ChIP-seq data; H.L.R., W.T.W. and Y.K. performed and interpreted the ChIP-seq data; J.E.K., N.B. and J.R.G. helped to analyse gut lymphocytes; T.S.D. and Q.C. helped to analyse CNS lymphocytes. G.E. provided the Rorc(γt)-GfpTG mice and made helpful suggestions; W.C. provided the Tgfbr1f/fCD4-Cre+ mice, contributed to the experimental design and data interpretation; Y.B., E.M.S. and D.J.C. contributed to the experimental design, data interpretation and made helpful suggestions. J.J.O'S. contributed to the experimental design, analysed and interpreted all acquired data and helped to write the manuscript.

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Correspondence to Kamran Ghoreschi or John J. O’Shea.

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Ghoreschi, K., Laurence, A., Yang, XP. et al. Generation of pathogenic TH17 cells in the absence of TGF-β signalling. Nature 467, 967–971 (2010). https://doi.org/10.1038/nature09447

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  1. Sergio Romagnani

    The demolished dogma

    Francesco Annunziato and Sergio Romagnani

    Department of Internal Medicine and DENOTHE Center, University of Florence, Italy

    Corresponding Author: Professor Sergio Romagnani, Department of Internal Medicine, University of Florence, Viale Pieraccini 6 Firenze-50134, Italy
    Ph. +39-055-4271492; Fax. +39-055-4271500
    E-mail: [email protected]
    In this paper, Ghoreschi et al.(1) definitively demolish the still ruling dogma of the critical role for TGF-beta in the generation of pathogenic TH17 cells. This study is of critical importance not only for the content, but also for its didactic and political significance in the field of immunology. TH17 cells were first recognized in mice and found to be induced by TGF-beta plus IL-6 (2-4), whereas in presence of TGF-beta alone the same naive TH cells developed into Foxp3+ T regulatory cells (2). Murine TH17 cells appeared to be pathogenic in different murine models of autoimmune disorders, whereas TH1 cells were rather thought to be protective (5). Studies in humans did not confirm the critical role for TGF-beta in TH17 differentiation (6,7). In particular, those performed in our laboratory showed a series of differences between the properties of murine and human TH17 cells (7-9). First, human TH17 cells expressed not only the IL-23 receptor (R) and the transcription factor Rorc, but also the TH1-related IL-12Rbeta2 and transcription factor T-bet. Second, several human TH cells produced both IL-17A and interferon (IFN)-gamma; third, IL-12 up-regulated T-bet expression by TH17 cells and induced them to shift to the TH1 phenotype (8). All together, these findings suggested both a developmental relationship between the TH1 and TH17 cell subsets and the flexibility of TH17 cells (8). Finally and most importantly, human memory TH17 cells were found to express both CCR6 and CD161 (7,8) and to originate from CCR6+CD161+IL-23R+ and Rorc+ CD4+ T-cell precursors from both umbilical cord blood and newborn thymus only in response to the combined activity of IL-1beta and IL-23 but in absence of TGF-beta (7). TGF-beta was only found to favor human TH17 differentiation because of its suppressive activity on T-bet expression and consequently on the development of TH1 cells (9). Three different papers were then published which supported the role of TGF-beta even in human TH17 differentiation (10-12) and suggested that in previous studies TGF-beta presence in serum-containing cultures had been underestimated. These findings received an enthusiastic comment and the expression of great relief because the apparent species-specific differences were only attributable to the naivety of the studies performed in humans (13). The study of Ghoreschi et al. (1) demonstrates that murine and human Th17. cells have the same development requirements but because of opposite reasons, since it becomes now clear that the apparent species-specific differences were due to the fact that studies in humans had more correctly depicted the origin of Th17. cells and that only Th17. cells shifting to the production of IFN-gamma can exhibit pathogenicity (14). Ghoreschi et al. (1) fully confirm indeed all our above mentioned findings (7-9), although inexplicably in their paper none of our studies was cited. The teaching coming from this interesting story and its political significance is that too often immunologists using mouse models ignore the importance of studies directly performed in humans and that, as it has recently been stated (15), to fully realize the potential benefits of immunology for human health it is necessary to place more attention to human studies and make major efforts to allow them to flourish.

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    14. Annunziato, F & Romagnani, S. Do studies in humans better depict Th1. cells ? Blood 114, 2213-2219, 2009
    15. Davis, M.M. A prescription for human immunology. Immunity 29, 835-838, 2008

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