Suppression of Th2 and Tfh immune reactions by Nr4a receptors in mature T reg cells

Takashi Sekiya, Taisuke Kondo, Takashi Shichita, Rimpei Morita, Hiroshi Ichinose, Akihiko Yoshimura

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Regulatory T (T reg) cells are central mediators of immune suppression. As such, T reg cells are characterized by a distinct pattern of gene expression, which includes up-regulation of immunosuppressive genes and silencing of inflammatory cytokine genes. Although an increasing number of transcription factors that regulate T reg cells have been identified, the mechanisms by which the T reg cell-specific transcriptional program is maintained and executed remain largely unknown. The Nr4a family of nuclear orphan receptors, which we recently identified as essential for the development of T reg cells, is highly expressed in mature T reg cells as well, suggesting that Nr4a factors play important roles even beyond T reg cell development. Here, we showed that deletion of Nr4a genes specifically in T reg cells caused fatal systemic immunopathology. Nr4a-deficient T reg cells exhibited global alteration of the expression of genes which specify the T reg cell lineage, including reduction of Foxp3 and Ikzf4. Furthermore, Nr4a deficiency abrogated T reg cell suppressive activities and accelerated conversion to cells with Th2 and follicular helper T (Tfh) effectorlike characteristics, with heightened expression of Th2 and Tfh cytokine genes. These findings demonstrate that Nr4a factors play crucial roles in mature T reg cells by directly controlling a genetic program indispensable for T reg cell maintenance and function.

Original languageEnglish
Pages (from-to)1623-1640
Number of pages18
JournalJournal of Experimental Medicine
Volume212
Issue number10
DOIs
Publication statusPublished - 2015 Sep 21

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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