The Pten/PI3K pathway governs the homeostasis of Vα14iNKT cells

Abstract

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 Vα14iNKT cells. A failure in the development of Vα14iNKT cells occurs in the LckCrePten thymus between stage 2 (CD44highNK1.1−) and stage 3 (CD44highNK1.1+), resulting in decreased numbers of peripheral Vα14iNKT cells. In vitro, Pten-deficient Vα14iNKT cells show reduced proliferation and cytokine secretion in response to αGalCer stimulation but enhanced inhibitory Ly49 receptor expression. Following interaction with dendritic cells (DCs) loaded with αGalCer, Pten-deficient Vα14iNKT cells demonstrate activation of PI3K. Indeed, the effects of the Pten mutation require intact function of the PI3K subunits p110γ and p110δ. In vivo, LckCrePten mice display reduced serum IFNγ after αGalCer administration. Importantly, Vα14iNKT 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 Vα14iNKT cells.