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A critical function for TGF-β signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells

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Abstract

The molecular mechanisms directing the development of 'natural' CD4+CD25+Foxp3+ regulatory T cells (Treg cells) in the thymus are not thoroughly understood. We show here that conditional deletion of transforming growth factor-β receptor I (TβRI) in T cells blocked the appearance of CD4+CD25+Foxp3+ thymocytes at postnatal days 3–5. Paradoxically, however, beginning 1 week after birth, the same TβRI-mutant mice showed accelerated expansion of thymic CD4+CD25+Foxp3+ populations. This rapid recovery of Foxp3+ thymocytes was attributable mainly to overproduction of and heightened responsiveness to interleukin 2, as genetic ablation of interleukin 2 in TβRI-mutant mice resulted in a complete absence of CD4+CD25+Foxp3+ cells from the thymus and periphery. Thus, transforming growth factor-β signaling is critical to the thymic development of natural CD4+CD25+Foxp3+ Treg cells.

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Figure 1: Deletion of TβRI blocks CD4+CD25+Foxp3+ thymocyte development.
Figure 2: Cell-autonomous requirement for TβRI in the development of CD4+CD25+Foxp3+ thymocytes.
Figure 3: Recovery and activated phenotype of CD4+CD25+Foxp3+ thymocytes in Tgfbr1f/fLck-Cre+ mice.
Figure 4: CD4+CD25+Foxp3+ thymocytes show more cycling and proliferation in response to IL-2 in the absence of TβRI.
Figure 5: Deletion of IL-2 results in a complete lack of CD4+CD25+Foxp3+ thymocytes in Tgfbr1f/fLck-Cre+ mice.
Figure 6: Requirement for both TGF-β signaling and IL-2 in CD4+CD25+Foxp3+ thymocyte development, demonstrated by bone marrow chimeras.
Figure 7: Peripheral CD4+CD25+Foxp3+ T cells are absent from and CD4+Foxp3 T cells have an activated phenotype in Tgfbr1f/fLck-Cre+Il2–/– mice.
Figure 8: Requirement for both TGF-β signaling and IL-2 in the development of peripheral CD4+CD25+Foxp3+ T cells, as shown by bone marrow chimeras.

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Change history

  • 04 May 2008

    In the version of this article initially published online, error bars in Figures 2b, 3b,c, 4b–d, 5b, 7b and 8b were incorrect. The error has been corrected for all versions of the article.

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Acknowledgements

We thank S.M. Wahl and E.M. Shevach for critically reading the manuscript; S. Karlsson (Lund University) for Tgfbr1f/f mice; and U.H. von Andrian for discussions about the anti-CD49d experiments. Supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research of the National Institutes of Health.

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Y.L. designed and did experiments, analyzed data and contributed to the writing of the manuscript; P.Z. designed and did experiments; S.P. and J.L. did experiments; A.B.K. provided critical materials and helped analyze data; and W.C. initiated and directed the research, designed experiments, analyzed data and wrote the manuscript.

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Correspondence to WanJun Chen.

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Liu, Y., Zhang, P., Li, J. et al. A critical function for TGF-β signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat Immunol 9, 632–640 (2008). https://doi.org/10.1038/ni.1607

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