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Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3

Nature Immunology volume 8, pages 277–284 (2007)Cite this article

Abstract

The transcription factor Foxp3 is required for the development of regulatory T cells (Treg cell). Here we report that induced ablation of a loxP-flanked Foxp3 allele in mature Treg cells resulted in the loss of their suppressive function in vivo and acquisition of the ability to produce interleukin 2 and T helper type 1 cytokines. Furthermore, after adoptive transfer in the absence of functional Treg cells into lymphopenic hosts, Treg cells with deletion of Foxp3 proliferated and were predominant among tissue-infiltrating T cells. In agreement with those results, we found deregulation of Foxp3 target gene expression after Foxp3 deletion. Thus, continued Foxp3 expression in mature Treg cells is needed to maintain the transcriptional and functional program established during Treg cell development.

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Figure 1: Deletion of a floxed Foxp3 allele in mature peripheral Treg cells induced after retroviral Cre expression.
Figure 2: Foxp3 ablation in mature Treg cells results in reversal of the characteristic CD25 and IL-7Rα expression pattern and acquisition of IL-2 and TH1 cytokine expression.
Figure 3: Loss of the Foxp3-dependent transcriptional program after deletion of Foxp3 in mature peripheral Treg cells.
Figure 4: Elimination of Foxp3 in peripheral Treg cells results in lower expression of putative trans-acting Treg 'suppressor effector' genes and upregulation of immune response–promoting genes.
Figure 5: Small numbers of Foxp3−CD25+ CD4+ T cells present in CD25+CD4+Foxp3+ T cell populations subjected to Cre-mediated deletion do not 'preferentially' expand their populations after adoptive transfer into T cell–deficient recipient mice.
Figure 6: Foxp3 ablation in mature Treg cells results in the loss of suppressor function.
Figure 7: Secondary lymphoid organs and non-lymphoid tissues of recipient mice have more YFP+Foxp3Δ T cells.

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Acknowledgements

We thank K. Forbush, L. Karpik, T. Chu and J. Lund for technical help; members of our laboratory for discussions; D. Livingston for the HR-MMPCreGFP retroviral vector; and F. Costantini for R26YFP mice. Supported by the National Institutes of Health (A.Y.R.), the Howard Hughes Medical Institute (A.Y.R.) and the Cancer Research Institute (L.M.W.).

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Authors and Affiliations

  1. Department of Immunology, University of Washington, Seattle, 98195, Washington, USA

    Luke M Williams & Alexander Y Rudensky

  2. Howard Hughes Medical Institute, University of Washington, Seattle, 98195, Washington, USA

    Alexander Y Rudensky

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Correspondence to Alexander Y Rudensky.

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Supplementary information

Supplementary Fig. 1

Cytokine expression after Foxp3 deletion. (PDF 85 kb)

Supplementary Fig. 2

Real-time PCR analysis of Foxp3 direct target gene expression after Foxp3 ablation. (PDF 52 kb)

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Williams, L., Rudensky, A. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol 8, 277–284 (2007). https://doi.org/10.1038/ni1437

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