title: Suppression of Th2 and Tfh immune reactions by Nr4a receptors in mature T reg cells.
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) effector-like 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.
authors: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan yoshimura@a6.keio.jp t-sekiya@z7.keio.jp.
authors: Takashi
authors: T
authors: Sekiya
authors: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors: Taisuke
authors: T
authors: Kondo
authors: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors: Takashi
authors: T
authors: Shichita
authors: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors: Rimpei
authors: R
authors: Morita
authors: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Kanagawa 226-8501, Japan.
authors: Hiroshi
authors: H
authors: Ichinose
authors: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology, Chiyoda-ku, Tokyo 102-0075, Japan yoshimura@a6.keio.jp t-sekiya@z7.keio.jp.
authors: Akihiko
authors: A
authors: Yoshimura
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D014158:Transcription, Genetic
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D009419:Nerve Tissue Proteins; C539818:Nr4a1 protein, mouse; C539883:Nr4a2 protein, mouse; C490411:Nr4a3 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; C118760:Zfpn1a4 protein, mouse; D015847:Interleukin-4