Deletion of PI3K-p85α gene impairs lineage commitment, terminal maturation, cytokine generation and cytotoxicity of NK cells
Deletion of PI3K-p85α gene impairs lineage commitment, terminal maturation, cytokine generation and cytotoxicity of NK cells
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DOI：
10.1038/gene.2008.45
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发表时间：
2008-09-01
影响因子：
5
通讯作者：
Malarkannan, S.
中科院分区：
文献类型：
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作者：
Awasthi, A.;Samarakoon, A.;Malarkannan, S.
IA类磷脂酰肌醇-3-激酶（PI 3 Ks）是在调节B和T细胞中的信号传导事件中重要的p85/p110异二聚体脂质激酶家族。然而，它们在自然杀伤（NK）细胞中的作用尚不清楚。在这里，使用缺乏调节性p85 α亚基及其可变剪接变体p55 α/p50 α（统称为p85 α（-/-））的小鼠，我们定义了PI 3 K在NK细胞发育和功能中的作用。p85 α（-/-）小鼠具有受损的谱系定型，导致骨髓和肝脏中NK细胞减少。p85 α（-/-）NK细胞显示Ly 49亚群特异性缺陷和CD 43表达降低。缺乏p85 a严重降低了NK介导的对肿瘤细胞的细胞毒性，代表“诱导自我”和“缺失自我”。更重要的是，NKG 2D和NK1.1受体介导的细胞因子和趋化因子生成在p85 α（-/-）NK细胞中显著受损。这些结果揭示了以前未被认识的作用p85 a的发展，终端成熟，细胞因子/趋化因子的产生和肿瘤清除的NK细胞。
Class IA phosphotidylinositol-3-kinases (PI3Ks) are a family of p85/p110 heterodimeric lipid kinases that are important in regulating signaling events in B and T cells. However, their role in natural killer (NK) cells is not understood. Here, using mice that lack the regulatory p85 alpha subunit and its alternatively spliced variants p55 alpha/p50 alpha (collectively termed as p85 alpha(-/-)), we defined the role of PI3K in NK cell development and function. p85 alpha(-/-) mice had impaired lineage commitment leading to reduced NK cellularity in the bone marrow and liver. p85 alpha(-/-) NK cells showed a defective Ly49 subset specification and a decreased expression of CD43. Lack of p85a severely reduced the NK-mediated cytotoxicity against tumor cells representing 'induced-self' and 'missing-self'. More importantly, NKG2D and NK1.1 receptor-mediated cytokine and chemokine generation was significantly compromised in p85 alpha(-/-) NK cells. These results reveal a previously unrecognized role of p85a in the development, terminal maturation, cytokine/chemokine generation and tumor clearance of NK cells.