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Foxp3-dependent programme of regulatory T-cell differentiation

Nature volume 445, pages 771–775 (2007)Cite this article

Abstract

Regulatory CD4+ T cells (Tr cells), the development of which is critically dependent on X-linked transcription factor Foxp3 (forkhead box P3), prevent self-destructive immune responses1. Despite its important role, molecular and functional features conferred by Foxp3 to Tr precursor cells remain unknown. It has been suggested that Foxp3 expression is required for both survival of Tr precursors as well as their inability to produce interleukin (IL)-2 and independently proliferate after T-cell-receptor engagement, raising the possibility that such ‘anergy’ and Tr suppressive capacity are intimately linked2,3,4. Here we show, by dissociating Foxp3-dependent features from those induced by the signals preceding and promoting its expression in mice, that the latter signals include several functional and transcriptional hallmarks of Tr cells. Although its function is required for Tr cell suppressor activity, Foxp3 to a large extent amplifies and fixes pre-established molecular features of Tr cells, including anergy and dependence on paracrine IL-2. Furthermore, Foxp3 solidifies Tr cell lineage stability through modification of cell surface and signalling molecules, resulting in adaptation to the signals required to induce and maintain Tr cells. This adaptation includes Foxp3-dependent repression of cyclic nucleotide phosphodiesterase 3B, affecting genes responsible for Tr cell homeostasis.

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Figure 1: Phenotype and frequency of cells transcribing the Foxp3 gfpko locus in Foxp3 gfpko/wt mice.
Figure 2: Foxp3-dependent suppression and lineage stability.
Figure 3: Foxp3-amplified gene expression constitutes a defining characteristic of thymic and peripheral T r cells.
Figure 4: Reduced PDE3B expression permits normal T r cell homoeostasis and T r -specific gene expression.

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Acknowledgements

We are grateful to all members of the Rudensky laboratory for discussions. We also thank K. Forbush, L. Karpik and T. Chu for help. This work was supported by grants from the Arthritis Foundation and the Leukemia and Lymphoma Society (M.A.G.) and grants from the National Institutes of Health (A.Y.R.). A.Y.R. is a Howard Hughes Medical Institute Investigator.

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  1. Marc A. Gavin

    Present address: Present address: Amgen Corporation, Seattle, Washington 98101, USA.,

Authors and Affiliations

  1. Departments of Immunology and,,

    Marc A. Gavin, Jeffrey P. Rasmussen, Jason D. Fontenot & Alexander Y. Rudensky

  2. Pharmacology, and the,,

    Valeria Vasta & Joseph A. Beavo

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

    Alexander Y. Rudensky

  4. National Heart, Lung, and Blood Institute, NIH, 9000 Rockville Pike, Bethesda, Maryland 20892, USA,

    Vincent C. Manganiello

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Correspondence to Alexander Y. Rudensky.

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Gavin, M., Rasmussen, J., Fontenot, J. et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445, 771–775 (2007). https://doi.org/10.1038/nature05543

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