The Pten/PI3K pathway governs the homeostasis of Valpha14iNKT cells.
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.
Kishimoto
Hiroyuki
H
Department of Molecular Biology, Akita University School of Medicine, Hondo 1-1-1, Akita 0108-543, Japan.
Ohteki
Toshiaki
T
Yajima
Nobuyuki
N
Kawahara
Koichi
K
Natsui
Miyuki
M
Kawarasaki
Satoru
S
Hamada
Koichi
K
Horie
Yasuo
Y
Kubo
Yoshiaki
Y
Arase
Seiji
S
Taniguchi
Masaru
M
Vanhaesebroeck
Bart
B
Mak
Tak Wah
TW
Nakano
Toru
T
Koyasu
Shigeo
S
Sasaki
Takehiko
T
Suzuki
Akira
A
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*
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