Nr4a Receptors Regulate Development and Death of Labile Treg Precursors to Prevent Generation of Pathogenic Self-Reactive Cells

Takashi Sekiya, Sana Hibino, Keita Saeki, Mitsuhiro Kanamori, Satoshi Takaki, Akihiko Yoshimura

Research output: Contribution to journalArticle

Abstract

Regulatory T (Treg) cells develop from a self-reactive, CD4-single positive (CD4SP) precursor cell pool. Thus, Treg-fated developing thymocytes are expected to possess the potential to generate pathogenic self-reactive cells. However, no such pathogenic conversion has been observed, indicating mechanisms of defense to prevent such a deleterious event. Here, we show that, after the initial developmental phase, the Nr4a family of nuclear receptors promotes the development of Treg cells by cooperating with other Treg cell developmental machineries, as well as by forming a reinforcing loop with Foxp3. Nr4a-deficient Treg-fated thymocytes survive and can elicit autoimmunity, highlighting their roles in elimination of developing Treg precursors that fail to complete their development. Our findings reveal that the defective development of Treg-fated thymocytes is a potential route for the generation of pathogenic self-reactive cells, which is normally suppressed by Nr4a factors at both developmental and cell death levels. Sekiya et al. find that developing precursors of Treg cells are a labile population compared to mature Treg cells and can convert to pathogenic self-reactive cells. They show that Nr4a family nuclear receptors prevent this pathogenic conversion of Treg precursors at the level of both development and cell death.

Original languageEnglish
Pages (from-to)1627-1638.e6
JournalCell Reports
Volume24
Issue number6
DOIs
Publication statusPublished - 2018 Aug 7

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Cell death
Regulatory T-Lymphocytes
Cytoplasmic and Nuclear Receptors
Thymocytes
Cell Death
Autoimmunity
Population

Keywords

  • Foxp3
  • immune tolerance
  • inflammatory cytokine
  • negative selection
  • Nr4a
  • Treg

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Nr4a Receptors Regulate Development and Death of Labile Treg Precursors to Prevent Generation of Pathogenic Self-Reactive Cells. / Sekiya, Takashi; Hibino, Sana; Saeki, Keita; Kanamori, Mitsuhiro; Takaki, Satoshi; Yoshimura, Akihiko.

In: Cell Reports, Vol. 24, No. 6, 07.08.2018, p. 1627-1638.e6.

Research output: Contribution to journalArticle

Sekiya, Takashi ; Hibino, Sana ; Saeki, Keita ; Kanamori, Mitsuhiro ; Takaki, Satoshi ; Yoshimura, Akihiko. / Nr4a Receptors Regulate Development and Death of Labile Treg Precursors to Prevent Generation of Pathogenic Self-Reactive Cells. In: Cell Reports. 2018 ; Vol. 24, No. 6. pp. 1627-1638.e6.
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