title: Transcriptional regulator Bhlhe40 works as a cofactor of T-bet in the regulation of IFN-γ production in iNKT cells.
abstract: Invariant natural killer T (iNKT) cells are a subset of innate-like T cells that act as important mediators of immune responses. In particular, iNKT cells have the ability to immediately produce large amounts of IFN-γ upon activation and thus initiate immune responses in various pathological conditions. However, molecular mechanisms that control IFN-γ production in iNKT cells are not fully understood. Here, we report that basic helix-loop-helix transcription factor family, member e40 (Bhlhe40), is an important regulator for IFN-γ production in iNKT cells. Bhlhe40 is highly expressed in stage 3 thymic iNKT cells and iNKT1 subsets, and the level of Bhlhe40 mRNA expression is correlated with Ifng mRNA expression in the resting state. Although Bhlhe40-deficient mice show normal iNKT cell development, Bhlhe40-deficient iNKT cells show significant impairment of IFN-γ production and antitumor effects. Bhlhe40 alone shows no significant effects on Ifng promoter activities but contributes to enhance T-box transcription factor Tbx21 (T-bet)-mediated Ifng promoter activation. Chromatin immunoprecipitation analysis revealed that Bhlhe40 accumulates in the T-box region of the Ifng locus and contributes to histone H3-lysine 9 acetylation of the Ifng locus, which is impaired without T-bet conditions. These results indicate that Bhlhe40 works as a cofactor of T-bet for enhancing IFN-γ production in iNKT cells.
authors.affiliation: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15 Nishi-7, Sapporo 060-0815, Japan; Division of Rheumatology, Endocrinology, and Nephrology, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Sapporo 060-0815, Japan; Japan Society for the Promotion of Science, 5-3-1 Koujimachi, Chiyoda-ku, Tokyo 102-0083, Japan;
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kanda
authors.affiliation: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15 Nishi-7, Sapporo 060-0815, Japan; Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa 216-8512, Japan;
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamanaka
authors.affiliation: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15 Nishi-7, Sapporo 060-0815, Japan; seino@igm.hokudai.ac.jp satoshi.kojo@riken.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kojo
authors.affiliation: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15 Nishi-7, Sapporo 060-0815, Japan;
authors.forename: Yuu
authors.initials: Y
authors.lastname: Usui
authors.affiliation: Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8553, Japan;
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Honda
authors.affiliation: Natural Science Center for Basic Research and Development, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8553, Japan;
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sotomaru
authors.affiliation: Laboratory for Immune Regulation, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Michishige
authors.initials: M
authors.lastname: Harada
authors.affiliation: Laboratory for Immune Regulation, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Taniguchi
authors.affiliation: Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa 216-8512, Japan;
authors.forename: Nao
authors.initials: N
authors.lastname: Suzuki
authors.affiliation: Division of Rheumatology, Endocrinology, and Nephrology, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Sapporo 060-0815, Japan;
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Atsumi
authors.affiliation: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15 Nishi-7, Sapporo 060-0815, Japan;
authors.forename: Haruka
authors.initials: H
authors.lastname: Wada
authors.affiliation: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15 Nishi-7, Sapporo 060-0815, Japan;
authors.forename: Muhammad
authors.initials: M
authors.lastname: Baghdadi
authors.affiliation: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15 Nishi-7, Sapporo 060-0815, Japan; seino@igm.hokudai.ac.jp satoshi.kojo@riken.jp.
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Seino
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology*; D007111:Immunity, Cellular / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000276:immunology*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D007371:Interferon-gamma; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C491539:Bhlhe40 protein, mouse; C000611649:IFNG protein, mouse
keywords: Bhlhe40; T-box transcription factor Tbx21; basic helix–loop–helix transcription factors; interferon-γ; natural killer T cells