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The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells

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  • Takashi Sekiya

    (Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.)

  • Ikkou Kashiwagi

    (Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.)

  • Naoko Inoue

    (Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.)

  • Rimpei Morita

    (Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.)

  • Shohei Hori

    (Research Unit for Immune Homeostasis, Research Center for Allergy and Immunology, RIKEN)

  • Herman Waldmann

    (Sir William Dunn School of Pathology)

  • Alexander Y. Rudensky

    (Howard Hughes Medical Institute and Immunology Program, Memorial Sloan-Kettering Cancer Center)

  • Hiroshi Ichinose

    (Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology)

  • Daniel Metzger

    (Department of Functional Genomics Institut de Génétique et Biologie Moléculaire et Cellulaire)

  • Pierre Chambon

    (Department of Functional Genomics Institut de Génétique et Biologie Moléculaire et Cellulaire)

  • Akihiko Yoshimura

    (Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
    Japan Science and Technology Agency (JST), CREST)

Abstract

Regulatory T cells (Tregs) have a central role in maintaining immune homoeostasis through various mechanisms. Although the Forkhead transcription factor Foxp3 defines the Treg cell lineage and functions, the molecular mechanisms of Foxp3 induction and maintenance remain elusive. Here we show that Foxp3 is one of the direct targets of Nr4a2. Nr4a2 binds to regulatory regions of Foxp3, where it mediates permissive histone modifications. Ectopic expression of Nr4a2 imparts Treg-like suppressive activity to naïve CD4+ T cells by inducing Foxp3 and by repressing cytokine production, including interferon-γ and interleukin-2. Deletion of Nr4a2 in T cells attenuates induction of Tregs and causes aberrant induction of Th1, leading to the exacerbation of colitis. Nr4a2-deficeint Tregs are prone to lose Foxp3 expression and have attenuated suppressive ability both in vitro and in vivo. Thus, Nr4a2 has the ability to maintain T-cell homoeostasis by regulating induction, maintenance and suppressor functions of Tregs, and by repression of aberrant Th1 induction.

Suggested Citation

  • Takashi Sekiya & Ikkou Kashiwagi & Naoko Inoue & Rimpei Morita & Shohei Hori & Herman Waldmann & Alexander Y. Rudensky & Hiroshi Ichinose & Daniel Metzger & Pierre Chambon & Akihiko Yoshimura, 2011. "The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells," Nature Communications, Nature, vol. 2(1), pages 1-12, September.
    • Handle: RePEc:nat:natcom:v:2:y:2011:i:1:d:10.1038_ncomms1272
    DOI: 10.1038/ncomms1272
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    1. Yasmin K. Alshoubaki & Bhavana Nayer & Yen-Zhen Lu & Ekaterina Salimova & Sin Nee Lau & Jean L. Tan & Daniela Amann-Zalcenstein & Peter F. Hickey & Gonzalo Monte-Nieto & Ajithkumar Vasanthakumar & Mik, 2024. "Tregs delivered post-myocardial infarction adopt an injury-specific phenotype promoting cardiac repair via macrophages in mice," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Jae-Won Cho & Seyeon Park & Gamin Kim & Heonjong Han & Hyo Sup Shim & Sunhye Shin & Yong-Soo Bae & Seong Yong Park & Sang-Jun Ha & Insuk Lee & Hye Ryun Kim, 2021. "Dysregulation of TFH-B-TRM lymphocyte cooperation is associated with unfavorable anti-PD-1 responses in EGFR-mutant lung cancer," Nature Communications, Nature, vol. 12(1), pages 1-16, December.

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