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

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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

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ASJC Scopus subject areas

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

Cite this

Sekiya, T., Kashiwagi, I., Inoue, N., Morita, R., Hori, S., Waldmann, H., Rudensky, A. Y., 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, 2(1), [269]. https://doi.org/10.1038/ncomms1272