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

Takashi Sekiya, Ikkou Kashiwagi, Naoko Inoue, Rimpei Morita, Shohei Hori, Herman Waldmann, Alexander Y. Rudensky, Hiroshi Ichinose, Daniel Metzger, Pierre Chambon and Akihiko Yoshimura ()
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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.

Nature Communications, 2011, vol. 2, issue 1, 1-12

Abstract: 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.

Date: 2011
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DOI: 10.1038/ncomms1272

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