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Foxp3-dependent programme of regulatory T-cell differentiation

Author

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  • Marc A. Gavin

    (Departments of Immunology and,
    Present address: Amgen Corporation, Seattle, Washington 98101, USA.)

  • Jeffrey P. Rasmussen

    (Departments of Immunology and,)

  • Jason D. Fontenot

    (Departments of Immunology and,)

  • Valeria Vasta

    (Pharmacology, and the,)

  • Vincent C. Manganiello

    (National Heart, Lung, and Blood Institute, NIH, 9000 Rockville Pike, Bethesda, Maryland 20892, USA)

  • Joseph A. Beavo

    (Pharmacology, and the,)

  • Alexander Y. Rudensky

    (Departments of Immunology and,
    Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA)

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.

Suggested Citation

  • Marc A. Gavin & Jeffrey P. Rasmussen & Jason D. Fontenot & Valeria Vasta & Vincent C. Manganiello & Joseph A. Beavo & Alexander Y. Rudensky, 2007. "Foxp3-dependent programme of regulatory T-cell differentiation," Nature, Nature, vol. 445(7129), pages 771-775, February.
  • Handle: RePEc:nat:nature:v:445:y:2007:i:7129:d:10.1038_nature05543
    DOI: 10.1038/nature05543
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    Cited by:

    1. Di Wu & Haomin Li & Mingwei Liu & Jun Qin & Yi Sun, 2022. "The Ube2m-Rbx1 neddylation-Cullin-RING-Ligase proteins are essential for the maintenance of Regulatory T cell fitness," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Tian Hong & Jianhua Xing & Liwu Li & John J Tyson, 2011. "A Mathematical Model for the Reciprocal Differentiation of T Helper 17 Cells and Induced Regulatory T Cells," PLOS Computational Biology, Public Library of Science, vol. 7(7), pages 1-13, July.
    3. Kerstin Johann & Toszka Bohn & Fatemeh Shahneh & Natascha Luther & Alexander Birke & Henriette Jaurich & Mark Helm & Matthias Klein & Verena K. Raker & Tobias Bopp & Matthias Barz & Christian Becker, 2021. "Therapeutic melanoma inhibition by local micelle-mediated cyclic nucleotide repression," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    4. Zhi Liu & Dong-Sung Lee & Yuqiong Liang & Ye Zheng & Jesse R. Dixon, 2023. "Foxp3 orchestrates reorganization of chromatin architecture to establish regulatory T cell identity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    5. Chelisa Cardinez & Yuwei Hao & Kristy Kwong & Ainsley R. Davies & Morgan B. Downes & Nadia A. Roberts & Jason D. Price & Raquel A. Hernandez & Jessica Lovell & Rochna Chand & Zhi-Ping Feng & Anselm En, 2024. "IKK2 controls the inflammatory potential of tissue-resident regulatory T cells in a murine gain of function model," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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