title: Notch 1 and Notch 2 synergistically regulate the differentiation and function of invariant NKT cells.
abstract: Invariant natural killer T cells are a distinct subset of T cells that exert Janus-like functions. Moreover, Notch signaling is known to have critical roles in the development and functions of T cells. However, it is not known whether Notch signaling contributes to the development or functions of invariant natural killer T cells. Here, we found that CD4-specific gene ablation of Notch 1 and Notch 2 (N1N2(-/-)) increased the number of invariant natural killer T cells in the thymus but decreased them in the liver. N1N2(-/-) mice showed impaired thymic maturation of invariant natural killer T cells from the NK1.1(-)CD44(+) to the NK1.1(+)CD44(+) stage, resulting in accumulation of NK1.1(-)CD44(+) invariant natural killer T cells in the thymus. Upon activation, hepatic invariant natural killer T cells from N1N2(-/-) mice produced lower cytokine levels and increased apoptosis versus wild-type invariant natural killer T cells. Furthermore, Notch 1/Notch 2-deficient, but not wild type, invariant natural killer T cells failed to promote antibody-induced arthritis in CD1d(-/-) mice. Unlike N1N2(-/-) mice, RBP-j(lox) (/) (lox) CD4-Cre mice showed similar percentages and numbers of thymic invariant natural killer T cells to wild-type mice but had defects in their homeostasis, maturation, and cytokine production in the liver. Taken together, our data indicate distinct effects of Notch signaling on invariant natural killer T cells in the thymus and liver, which are at least partly independent of RBP-j in the thymus.
authors.affiliation: *Department of Pathology, Ischemic/Hypoxia Institute, and Laboratory of Immune Regulation, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea; and Department of Immunology and Parasitology, Institute of Health Biosciences, University of Tokushima Graduate School, Kuramoto, Tokushima, Japan.
authors.forename: Sae Jin
authors.initials: SJ
authors.lastname: Oh
authors.affiliation: *Department of Pathology, Ischemic/Hypoxia Institute, and Laboratory of Immune Regulation, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea; and Department of Immunology and Parasitology, Institute of Health Biosciences, University of Tokushima Graduate School, Kuramoto, Tokushima, Japan.
authors.forename: Sehee
authors.initials: S
authors.lastname: Ahn
authors.affiliation: *Department of Pathology, Ischemic/Hypoxia Institute, and Laboratory of Immune Regulation, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea; and Department of Immunology and Parasitology, Institute of Health Biosciences, University of Tokushima Graduate School, Kuramoto, Tokushima, Japan.
authors.forename: Young-Hee
authors.initials: YH
authors.lastname: Jin
authors.affiliation: *Department of Pathology, Ischemic/Hypoxia Institute, and Laboratory of Immune Regulation, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea; and Department of Immunology and Parasitology, Institute of Health Biosciences, University of Tokushima Graduate School, Kuramoto, Tokushima, Japan.
authors.forename: Chieko
authors.initials: C
authors.lastname: Ishifune
authors.affiliation: *Department of Pathology, Ischemic/Hypoxia Institute, and Laboratory of Immune Regulation, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea; and Department of Immunology and Parasitology, Institute of Health Biosciences, University of Tokushima Graduate School, Kuramoto, Tokushima, Japan.
authors.forename: Ji Hyung
authors.initials: JH
authors.lastname: Kim
authors.affiliation: *Department of Pathology, Ischemic/Hypoxia Institute, and Laboratory of Immune Regulation, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea; and Department of Immunology and Parasitology, Institute of Health Biosciences, University of Tokushima Graduate School, Kuramoto, Tokushima, Japan doohyun@snu.ac.kr yasutomo@tokushima-u.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Yasutomo
authors.affiliation: *Department of Pathology, Ischemic/Hypoxia Institute, and Laboratory of Immune Regulation, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea; and Department of Immunology and Parasitology, Institute of Health Biosciences, University of Tokushima Graduate School, Kuramoto, Tokushima, Japan doohyun@snu.ac.kr yasutomo@tokushima-u.ac.jp.
authors.forename: Doo Hyun
authors.initials: DH
authors.lastname: Chung
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000235:genetics / Q000276:immunology; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000235:genetics / Q000276:immunology; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology*; D051881:Receptor, Notch1 / Q000235:genetics / Q000276:immunology*; D051883:Receptor, Notch2 / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
chemical_list: D055610:Antigens, CD1d; D000950:Antigens, Ly; C584692:CD1d antigen, mouse; C527211:Klrb1c protein, mouse; D055651:NK Cell Lectin-Like Receptor Subfamily B; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; D051881:Receptor, Notch1; D051883:Receptor, Notch2
keywords: RBP-j; arthritis; cytokines