title: Development of chronic allergic responses by dampening Bcl6-mediated suppressor activity in memory T helper 2 cells.
abstract: Mice deficient in the transcriptional repressor B-cell CLL/lymphoma 6 (Bcl6) exhibit similar T helper 2 (TH2) immune responses as patients with allergic diseases. However, the molecular mechanisms underlying Bcl6-directed regulation of TH2 cytokine genes remain unclear. We identified multiple Bcl6/STAT binding sites (BSs) in TH2 cytokine gene loci. We found that Bcl6 is modestly associated with the BSs, and it had no significant effect on cytokine production in newly differentiated TH2 cells. Contrarily, in memory TH2 (mTH2) cells derived from adaptively transferred TH2 effectors, Bcl6 outcompeted STAT5 for binding to TH2 cytokine gene loci, particularly Interleukin4 (Il4) loci, and attenuated GATA binding protein 3 (GATA3) binding to highly conserved intron enhancer regions in mTH2 cells. Bcl6 suppressed cytokine production epigenetically in mTH2 cells to negatively tune histone acetylation at TH2 cytokine gene loci, including Il4 loci. In addition, IL-33, a pro-TH2 cytokine, diminished Bcl6's association with loci to which GATA3 recruitment was inversely augmented, resulting in altered IL-4, but not IL-5 and IL-13, production in mTH2 cells but no altered production in newly differentiated TH2 cells. Use of a murine asthma model that generates high levels of pro-TH2 cytokines, such as IL-33, suggested that the suppressive function of Bcl6 in mTH2 cells is abolished in severe asthma. These findings indicate a role of the interaction between TH2-promoting factors and Bcl6 in promoting appropriate IL-4 production in mTH2 cells and suggest that chronic allergic diseases involve the TH2-promoting factor-mediated functional breakdown of Bcl6, resulting in allergy exacerbation.
authors.affiliation: Department of Respirology (B2), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ogasawara
authors.affiliation: Department of Biomedical Science (M14), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hatano
authors.affiliation: Department of Developmental Genetics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Hisae
authors.initials: H
authors.lastname: Satake
authors.affiliation: Department of Respirology (B2), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Ikari
authors.affiliation: Department of Biomedical Science (M14), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Toshibumi
authors.initials: T
authors.lastname: Taniguchi
authors.affiliation: Department of Reproductive Medicine (G4), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Nobuhide
authors.initials: N
authors.lastname: Tsuruoka
authors.affiliation: Department of Biomedical Science (M14), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Haruko
authors.initials: H
authors.lastname: Watanabe-Takano
authors.affiliation: Biomedical Research Center, Chiba University, Chiba 260-8670, Japan.
authors.forename: Lisa
authors.initials: L
authors.lastname: Fujimura
authors.affiliation: Department of Biomedical Science (M14), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Akemi
authors.initials: A
authors.lastname: Sakamoto
authors.affiliation: Department of Respiratory Medicine and Clinical Immunology, Dokkyo Medical University, Koshigaya Hospital, Saitama 343-0845, Japan.
authors.forename: Hirokuni
authors.initials: H
authors.lastname: Hirata
authors.affiliation: Department of Respiratory Medicine and Clinical Immunology, Dokkyo Medical University, Koshigaya Hospital, Saitama 343-0845, Japan.
authors.forename: Kumiya
authors.initials: K
authors.lastname: Sugiyama
authors.affiliation: Department of Respiratory Medicine and Clinical Immunology, Dokkyo Medical University, Koshigaya Hospital, Saitama 343-0845, Japan.
authors.forename: Yasutsugu
authors.initials: Y
authors.lastname: Fukushima
authors.affiliation: Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakae
authors.affiliation: Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Saito
authors.affiliation: Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Department of Rheumatology, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kurasawa
authors.affiliation: Department of Respirology (B2), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tatsumi
authors.affiliation: Department of Developmental Genetics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tokuhisa
authors.affiliation: Department of Biomedical Science (M14), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; masaa@dokkyomed.ac.jp.|Department of Developmental Genetics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.|Department of Rheumatology, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan.
authors.forename: Masafumi
authors.identifier: 0000-0002-5169-7536
authors.initials: M
authors.lastname: Arima
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D006657:Histones / Q000378:metabolism; D007073:Immunoglobulin E / Q000097:blood; D008070:Lipopolysaccharides / Q000276:immunology; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D016207:Cytokines; D006657:Histones; D008070:Lipopolysaccharides; D051560:Proto-Oncogene Proteins c-bcl-6; D007073:Immunoglobulin E; D010047:Ovalbumin
keywords: Bcl6; asthma; memory TH2 cells