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, Akihiko Yoshimura

Research output: Contribution to journalArticle

83 Citations (Scopus)

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.

Original languageEnglish
Article number269
JournalNature Communications
Volume2
Issue number1
DOIs
Publication statusPublished - 2011

Fingerprint

Orphan Nuclear Receptors
T-cells
induction
Regulatory T-Lymphocytes
T-Lymphocytes
Homeostasis
Histone Code
homeostasis
Maintenance
Forkhead Transcription Factors
Nucleic Acid Regulatory Sequences
maintenance
Cell Lineage
Colitis
Interferons
Interleukin-2
interferon
interleukins
suppressors
deletion

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells. / Sekiya, Takashi; Kashiwagi, Ikkou; Inoue, Naoko; Morita, Rimpei; Hori, Shohei; Waldmann, Herman; Rudensky, Alexander Y.; Ichinose, Hiroshi; Metzger, Daniel; Chambon, Pierre; Yoshimura, Akihiko.

In: Nature Communications, Vol. 2, No. 1, 269, 2011.

Research output: Contribution to journalArticle

Sekiya, T, Kashiwagi, I, Inoue, N, Morita, R, Hori, S, Waldmann, H, Rudensky, AY, Ichinose, H, Metzger, D, Chambon, P & Yoshimura, A 2011, 'The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells', Nature Communications, vol. 2, no. 1, 269. https://doi.org/10.1038/ncomms1272
Sekiya, Takashi ; Kashiwagi, Ikkou ; Inoue, Naoko ; Morita, Rimpei ; Hori, Shohei ; Waldmann, Herman ; Rudensky, Alexander Y. ; Ichinose, Hiroshi ; Metzger, Daniel ; Chambon, Pierre ; Yoshimura, Akihiko. / The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells. In: Nature Communications. 2011 ; Vol. 2, No. 1.
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