title: The Pten/PI3K pathway governs the homeostasis of Valpha14iNKT cells.
abstract: The tumor suppressor PTEN is mutated in many human cancers. We previously used the Cre-loxP system to generate mice (LckCrePten mice) with a Pten mutation in T-lineage cells. Here we describe the phenotype of Pten-deficient Valpha14iNKT cells. A failure in the development of Valpha14iNKT cells occurs in the LckCrePten thymus between stage 2 (CD44(high)NK1.1(-)) and stage 3 (CD44(high)NK1.1(+)), resulting in decreased numbers of peripheral Valpha14iNKT cells. In vitro, Pten-deficient Valpha14iNKT cells show reduced proliferation and cytokine secretion in response to alphaGalCer stimulation but enhanced inhibitory Ly49 receptor expression. Following interaction with dendritic cells (DCs) loaded with alphaGalCer, Pten-deficient Valpha14iNKT cells demonstrate activation of PI3K. Indeed, the effects of the Pten mutation require intact function of the PI3K subunits p110gamma and p110delta. In vivo, LckCrePten mice display reduced serum IFNgamma after alphaGalCer administration. Importantly, Valpha14iNKT cell-mediated protection against the metastasis of melanoma cells to the lung was impaired in the absence of Pten. Thus, the Pten/PI3K pathway is indispensable for the homeostasis and antitumor surveillance function of Valpha14iNKT cells.
authors.affiliation: Department of Molecular Biology, Akita University School of Medicine, Hondo 1-1-1, Akita 0108-543, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kishimoto
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Ohteki
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yajima
authors.forename: Koichi
authors.initials: K
authors.lastname: Kawahara
authors.forename: Miyuki
authors.initials: M
authors.lastname: Natsui
authors.forename: Satoru
authors.initials: S
authors.lastname: Kawarasaki
authors.forename: Koichi
authors.initials: K
authors.lastname: Hamada
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Horie
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kubo
authors.forename: Seiji
authors.initials: S
authors.lastname: Arase
authors.forename: Masaru
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.forename: Tak Wah
authors.initials: TW
authors.lastname: Mak
authors.forename: Toru
authors.initials: T
authors.lastname: Nakano
authors.forename: Shigeo
authors.initials: S
authors.lastname: Koyasu
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
authors.forename: Akira
authors.initials: A
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D003713:Dendritic Cells / Q000276:immunology; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D018960:Hyaluronan Receptors / Q000276:immunology; D007157:Immunologic Surveillance / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D055651:NK Cell Lectin-Like Receptor Subfamily B; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D055630:Receptors, NK Cell Lectin-Like; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000950:Antigens, Ly; D000954:Antigens, Surface; D058534:Class I Phosphatidylinositol 3-Kinases; D018960:Hyaluronan Receptors; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D016693:Receptors, Antigen, T-Cell, alpha-beta; D055630:Receptors, NK Cell Lectin-Like; C476399:Cd44 protein, mouse; C527203:KLRB1 protein, human; C527211:Klrb1c protein, mouse; C421683:Pik3cd protein, mouse; C487757:Pten protein, mouse