The Nuclear Orphan Receptor Nr4a2 Induces Foxp3 and Regulates Differentiation of CD4+ T Cells

Overview

Journal Nat Commun

Specialty Biology

Date 2011 Apr 7

PMID 21468021

Citations 109

Authors

Takashi Sekiya

Ikkou Kashiwagi

Naoko Inoue

Rimpei Morita

Shohei Hori

Herman Waldmann

Alexander Y Rudensky

Hiroshi Ichinose

Daniel Metzger

Pierre Chambon

Akihiko Yoshimura

Affiliations

Soon will be listed here.

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.

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