Regulation of peripheral Th/Treg differentiation and suppression of airway inflammation by Nr4a transcription factors

Takashi Sekiya, Shizuko Kagawa, Katsunori Masaki, Koichi Fukunaga, Akihiko Yoshimura, Satoshi Takaki

Research output: Contribution to journalArticlepeer-review

Abstract

Helper T (Th) and regulatory T (Treg) cell differentiation programs promote the eradication of pathogens, while minimizing adverse immune reactions. Here, we found that Nr4a family of nuclear receptors supports Treg cell induction and represses Th1 and Th2 cell differentiation from naive CD4+ T cells. Nr4a factors are transiently induced in CD4+ T cells immediately after antigen stimulation, thereby mediating epigenetic changes. In differentiating Treg cells, Nr4a factors mainly upregulated the early responsive genes in the Treg cell-specifying gene set, either directly or in cooperation with Ets family transcription factors. In contrast, Nr4a factors repressed AP-1 activity by interrupting a positive feedback loop for Batf factor expression, thus suppressing Th2 cell-associated genes. In an allergic airway inflammation model, Nr4a factors suppressed the pathogenesis, mediating oral tolerance. Lastly, pharmacological activation of an engineered Nr4a molecule prevented allergic airway inflammation, indicating that Nr4a factors may be novel therapeutic targets for inflammatory diseases.

Original languageEnglish
Article number102166
JournaliScience
Volume24
Issue number3
DOIs
Publication statusPublished - 2021 Mar 19

Keywords

  • Biological Sciences
  • Cell Biology
  • Immunology

ASJC Scopus subject areas

  • General

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