title: The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells.
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.
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sekiya
authors.forename: Ikkou
authors.initials: I
authors.lastname: Kashiwagi
authors.forename: Naoko
authors.initials: N
authors.lastname: Inoue
authors.forename: Rimpei
authors.initials: R
authors.lastname: Morita
authors.forename: Shohei
authors.initials: S
authors.lastname: Hori
authors.forename: Herman
authors.initials: H
authors.lastname: Waldmann
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Rudensky
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ichinose
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics / Q000276:immunology*; D011485:Protein Binding; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2