The Pten/PI3K pathway governs the homeostasis of Vα14iNKT cells
The Pten/PI3K pathway governs the homeostasis of Vα14iNKT cells
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DOI：
10.1182/blood-2006-07-038059
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发表时间：
2007-04-15
期刊：
影响因子：
20.3
通讯作者：
Suzuki, Akira
中科院分区：
文献类型：
--
作者：
Kishimoto, Hiroyuki;Ohteki, Toshiaki;Suzuki, Akira
肿瘤抑制因子PTEN在许多人类癌症中发生突变。我们先前使用Cre-loxP系统来产生在T谱系细胞中具有Pten突变的小鼠（LckCrePten小鼠）。在这里，我们描述了Pten缺陷V α 14 iNKT细胞的表型。在第2阶段（CD 44（高）NK1.1（-））和第3阶段（CD 44（高）NK1.1（+））之间的LckCrePten胸腺中发生V α 14 iNKT细胞发育失败，导致外周V α 14 iNKT细胞数量减少。在体外，Pten缺陷的V α 14 iNKT细胞显示响应于α GalCer刺激的增殖和细胞因子分泌减少，但抑制性Ly 49受体表达增强。在与负载有aGalCer的树突状细胞（DC）相互作用后，Pten缺陷的V a14 iNKT细胞显示PI 3 K的活化。事实上，Pten突变的作用需要PI 3 K亚基p110 γ和p110 δ的完整功能。在体内，LckCrePten小鼠在α GalCer施用后显示出降低的血清IFN γ。重要的是，在Pten不存在的情况下，V α 14 iNKT细胞介导的针对黑素瘤细胞转移至肺的保护受损。因此，Pten/PI 3 K途径对于V α 14 iNKT细胞的稳态和抗肿瘤监视功能是不可或缺的。
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 V alpha 14iNKT cells. A failure in the development of V alpha 14iNKT 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 V alpha 14iNKT cells. In vitro, Pten-deficient V alpha 14iNKT cells show reduced proliferation and cytokine secretion in response to alpha GalCer stimulation but enhanced inhibitory Ly49 receptor expression. Following interaction with dendritic cells (DCs) loaded with alpha GalCer, Pten-deficient V alpha 14iNKT cells demonstrate activation of PI3K. Indeed, the effects of the Pten mutation require intact function of the PI3K subunits p110 gamma and p110 delta. In vivo, LckCrePten mice display reduced serum IFN gamma after alpha GalCer administration. Importantly, V alpha 14iNKT 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 V alpha 14iNKT cells.