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IL-4 inhibits TGF-β-induced Foxp3+ T cells and, together with TGF-β, generates IL-9+ IL-10+ Foxp3 effector T cells

Nature Immunology volume 9, pages 13471355 (2008) | Download Citation

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  • An Erratum to this article was published on 01 May 2009

This article has been updated

Abstract

Transcription factor Foxp3 is critical for generating regulatory T cells (Treg cells). Transforming growth factor-β (TGF-β) induces Foxp3 and suppressive Treg cells from naive T cells, whereas interleukin 6 (IL-6) inhibits the generation of inducible Treg cells. Here we show that IL-4 blocked the generation of TGF-β-induced Foxp3+ Treg cells and instead induced a population of T helper cells that produced IL-9 and IL-10. The IL-9+IL-10+ T cells demonstrated no regulatory properties despite producing abundant IL-10. Adoptive transfer of IL-9+IL-10+ T cells into recombination-activating gene 1–deficient mice induced colitis and peripheral neuritis, the severity of which was aggravated if the IL-9+IL-10+ T cells were transferred with CD45RBhi CD4+ effector T cells. Thus IL-9+IL-10+ T cells lack suppressive function and constitute a distinct population of helper-effector T cells that promote tissue inflammation.

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Change history

  • 09 April 2009

    In the version of this article initially published, graph axes are mislabeled in Figures 1e, 2d and 2e, and a gene symbol is misidentified in the legend to Figure 2. The correct axis labels should be as follows: Figure 1e, middle right and far right vertical axes should end “(relative x 103)”; Figure 2d,e, left vertical axes should read “Il9 mRNA (relative x 102)”; Figure 2e, right vertical axis should read “Il10 mRNA (relative)”; and Figure 2e, horizontal axes should read “WT” (in place of “Foxp3-GFP”) and “GATA3-KO” (in place of “STAT6-KO.Fox3-GFP”). The legend for Figure 2d should state “relative to Hprt1 mRNA” and the legend to Figure 2e should have that phrase removed. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank D. Kozoriz, R. Chandwaskar and D. Lee for cell sorting and technical assistance; and R. Flavell (Yale University School of Medicine) for IL-10–GFP mice. Supported by the US National Institutes of Health (R01AI073542-01 to M.O., and 1R01NS045937-01, 2R01NS35685-06, 2R37NS30843-11, 1R01A144880-03, 2P01A139671-07, 1P01NS38037-04, 1R01NS046414 and a Javits Neuroscience Investigator Award to V.K.K.), the National Multiple Sclerosis Society (RG-2571-D-9 to V.K.K. and RG-3882-A-1 to M.O.), the Juvenile Diabetes Research Foundation Center for Immunological Tolerance at Harvard Medical School, and the National Multiple Sclerosis Society, New York (A.A. and V.D.).

Author information

Author notes

    • Valérie Dardalhon
    •  & Amit Awasthi

    These authors contributed equally to this work.

Affiliations

  1. Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Cambridge, Massachusetts 02139, USA.

    • Valérie Dardalhon
    • , Amit Awasthi
    • , Hyoung Kwon
    • , George Galileos
    •  & Mohamed Oukka
  2. Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Valérie Dardalhon
    • , Amit Awasthi
    • , Meike Mitsdoerffer
    • , Wassim Elyaman
    • , Samia Khoury
    •  & Vijay K Kuchroo
  3. Transplant Research Center, Beth Israel Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Wenda Gao
    •  & Terry B Strom
  4. Palo Alto Veteran's Administration Health Care System and Department of Pathology, Stanford University School of Medicine, Palo Alto, California 94304, USA.

    • Raymond A Sobel
  5. Division of Pediatric Hematology-Oncology, Children's Hospital, Department of Pediatric Oncology, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • I-Cheng Ho

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Contributions

V.D. and A.A. performed and designed the experiments, collected the data and contributed to the writing of the manuscript; H.K. and G.G. helped with the immunoprecipitation assays; W.G. and T.B.S. checked Foxp3 expression in IL-4-transgenic T cells; R.A.S. did the pathology analysis; M.M. diagnosed the neurological signs found in RAG-1–reconstituted mice; W.E. and S.K. helped in the studies using anti-IL-9; I.-C.H. generated and provided conditional GATA-3-deficient mice; M.O. designed experiments; V.K.K. designed the experiments, supervised the study and edited the manuscript.

Corresponding authors

Correspondence to Mohamed Oukka or Vijay K Kuchroo.

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DOI

https://doi.org/10.1038/ni.1677

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