Guo Hailong, Samarakoon Asanga, Vanhaesebroeck Bart, Malarkannan Subramaniam
Laboratory of Molecular Immunology, Blood Research Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
J Exp Med. 2008 Sep 29;205(10):2419-35. doi: 10.1084/jem.20072327. Epub 2008 Sep 22.
Phosphatidylinositol 3-kinases (PI3Ks) play a critical role in regulating B cell receptor- and T cell receptor-mediated signaling. However, their role in natural killer (NK) cell development and functions is not well understood. Using mice expressing p110 delta(D910A), a catalytically inactive p110 delta, we show that these mice had reduced NK cellularity, defective Ly49C and Ly49I NK subset maturation, and decreased CD27(High) NK numbers. p110 delta inactivation marginally impaired NK-mediated cytotoxicity against tumor cells in vitro and in vivo. However, NKG2D, Ly49D, and NK1.1 receptor-mediated cytokine and chemokine generation by NK cells was severely affected in these mice. Further, p110 delta(D910A/D910A) NK cell-mediated antiviral responses through natural cytotoxicity receptor 1 were reduced. Analysis of signaling events demonstrates that p110 delta(D910A/D910A) NK cells had a reduced c-Jun N-terminal kinase 1/2 phosphorylation in response to NKG2D-mediated activation. These results reveal a previously unrecognized role of PI3K-p110 delta in NK cell development and effector functions.
磷脂酰肌醇3激酶（PI3Ks）在调节B细胞受体和T细胞受体介导的信号传导中起关键作用。然而，它们在自然杀伤（NK）细胞发育和功能中的作用尚未得到充分了解。使用表达p110δ（D910A）（一种催化失活的p110δ）的小鼠，我们发现这些小鼠的NK细胞数量减少，Ly49C和Ly49I NK亚群成熟缺陷，以及CD27（高）NK细胞数量减少。p110δ失活在体外和体内对NK介导的针对肿瘤细胞的细胞毒性有轻微损害。然而，这些小鼠中NK细胞通过NKG2D、Ly49D和NK1.1受体介导的细胞因子和趋化因子生成受到严重影响。此外，p110δ（D910A/D910A）NK细胞通过自然细胞毒性受体1介导的抗病毒反应减少。信号事件分析表明，p110δ（D910A/D910A）NK细胞在响应NKG2D介导的激活时，c-Jun N末端激酶1/2磷酸化减少。这些结果揭示了PI3K-p110δ在NK细胞发育和效应功能中以前未被认识的作用。
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