title: Gfi1, a transcriptional repressor, inhibits the induction of the T helper type 1 programme in activated CD4 T cells.
abstract: A transcriptional repressor Gfi1 promotes T helper type 2 (Th2) cell development and inhibits Th17 and inducible regulatory T-cell differentiation. However, the role of Gfi1 in regulating Th1 cell differentiation and the Th1-type immune response remains to be investigated. We herein demonstrate that Gfi1 inhibits the induction of the Th1 programme in activated CD4 T cells. The activated Gfi1-deficient CD4 T cells spontaneously develop into Th1 cells in an interleukin-12- and interferon-γ-independent manner. The increase of Th1-type immune responses was confirmed in vivo in Gfi1-deficient mice using a murine model of nickel allergy and delayed-type hypersensitivity (DTH). The expression levels of Th1-related transcription factors were found to increase in Gfi1-deficient activated CD4 T cells. Tbx21, Eomes and Runx2 were identified as possible direct targets of Gfi1. Gfi1 binds to the Tbx21, Eomes and Runx2 gene loci and reduces the histone H3K4 methylation levels in part by modulating Lsd1 recruitment. Together, these findings demonstrate a novel regulatory role of Gfi1 in the regulation of the Th1-type immune response.
authors.affiliation: Department of Haematology, Clinical Immunology and Infectious Diseases, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.|Department of Translational Immunology, Translational Research Center, Ehime University Hospital, Toon, Ehime, Japan.
authors.forename: Junpei
authors.initials: J
authors.lastname: Suzuki
authors.affiliation: Department of Immunology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
authors.forename: Saho
authors.initials: S
authors.lastname: Maruyama
authors.affiliation: Division of Fundamental Medical Technology, Department of Medical Technology, Ehime Prefectural University of Health Science, Iyo-gun, Ehime, Japan.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tamauchi
authors.affiliation: Department of Translational Immunology, Translational Research Center, Ehime University Hospital, Toon, Ehime, Japan.|Department of Immunology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.|Division of Immune Regulation, Department of Proteo-Inovation, Proteo-Science Centre, Ehime University, Matsuyama, Ehime, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuwahara
authors.affiliation: Department of Immunology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Horiuchi
authors.affiliation: Department of Immunology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
authors.forename: Masumi
authors.initials: M
authors.lastname: Mizuki
authors.affiliation: Department of Immunology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.|Division of Cell-Free Sciences, Department of Proteo-Research, Proteo-Science Centre, Ehime University, Matsuyama, Ehime, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Ochi
authors.affiliation: Division of Cell-Free Sciences, Department of Proteo-Research, Proteo-Science Centre, Ehime University, Matsuyama, Ehime, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Sawasaki
authors.affiliation: Molecular and Cellular Immunoregulation Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
authors.forename: Jinfang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Haematology, Clinical Immunology and Infectious Diseases, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Yasukawa
authors.affiliation: Department of Translational Immunology, Translational Research Center, Ehime University Hospital, Toon, Ehime, Japan.|Department of Immunology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.|Division of Immune Regulation, Department of Proteo-Inovation, Proteo-Science Centre, Ehime University, Matsuyama, Ehime, Japan.
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Yamashita
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D056466:Histone Demethylases / Q000037:antagonists & inhibitors; D006657:Histones / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology*; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011485:Protein Binding; D020825:T-Box Domain Proteins / Q000235:genetics; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000098815:T-bet Transcription Factor
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D016207:Cytokines; D004268:DNA-Binding Proteins; C491198:Eomes protein, mouse; C079873:Gfi1 protein, mouse; D006657:Histones; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D007371:Interferon-gamma; D056466:Histone Demethylases; C504076:KDM1a protein, mouse
keywords: T helper type 1 differentiation; T helper type 1 immune response; epigenetics; histone H3K4 methylation