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TGF-β induces the expression of the adaptor Ndfip1 to silence IL-4 production during iTreg cell differentiation

Nature Immunology volume 13, pages 77–85 (2012)Cite this article

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Abstract

Mice deficient in the adaptor Ndfip1 develop inflammation at sites of environmental antigen exposure. We show here that such mice had fewer inducible regulatory T cells (iTreg cells). In vitro, Ndfip1-deficient T cells expressed normal amounts of the transcription factor Foxp3 during the first 48 h of iTreg cell differentiation; however, this expression was not sustained. Abortive Foxp3 expression was caused by production of interleukin 4 (IL-4) by Ndfip1−/− cells. We found that Ndfip1 expression was transiently upregulated during iTreg cell differentiation in a manner dependent on transforming growth factor-β (TGF-β). Once expressed, Ndfip1 promoted degradation of the transcription factor JunB mediated by the E3 ubiquitin ligase Itch, thus preventing IL-4 production. On the basis of our data, we propose that TGF-β signaling induces Ndfip1 expression to silence IL-4 production, thus permitting iTreg cell differentiation.

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Figure 1: Lower frequency of iTreg cells in the small bowel of Ndfip1−/− mice.
Figure 2: Impaired conversion of naive Ndfip1-deficient T cells into iTreg cells.
Figure 3: Ndfip1−/− and itchy mutant T cells are defective in conversion into iTreg cells.
Figure 4: Foxp3 expression decreases in Ndfip1−/− T cells after day 2.
Figure 5: Depletion of IL-4 restores the conversion in Ndfip1- and Itch-deficient T cells into iTreg cell.
Figure 6: Less inflammatory disease in Ndfip1−/− mice lacking IL-4.
Figure 7: Ndfip1 expression peaks early during iTreg cell differentiation to attenuate JunB expression.

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Acknowledgements

We thank H. Ramon for discussions and for help with setting up iTreg cell culture conditions; A. Bhandoola for critical reading of the manuscript; J.K. Burkhardt for discussions; A. Laroche for technical assistance; and the staff of the flow cytometry core at the University of Pennsylvania. Supported by the U.S. National Institutes of Health (RO3 AR057144, 1F32AI085837 and R01AI093566).

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Authors and Affiliations

  1. Cell Pathology Division, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Allison M Beal, Erin A Nowelsky & Paula M Oliver

  2. University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania, USA

    Natalia Ramos-Hernández, Chris R Riling & Paula M Oliver

  3. Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Paula M Oliver

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Contributions

A.M.B. designed and did experiments and wrote the manuscript; N.R.-H., C.R.R. and E.A.N. did experiments and contributed data; and P.M.O. designed experiments and wrote the manuscript.

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Correspondence to Paula M Oliver.

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Beal, A., Ramos-Hernández, N., Riling, C. et al. TGF-β induces the expression of the adaptor Ndfip1 to silence IL-4 production during iTreg cell differentiation. Nat Immunol 13, 77–85 (2012). https://doi.org/10.1038/ni.2154

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