期刊
GENES AND IMMUNITY
卷 9, 期 6, 页码 522-535出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/gene.2008.45
关键词
NK cell; NKG2D; PI3K; p85 alpha
资金
- ACS [RSG-02-172-LIB]
- ROTRF [111662730]
- NIH [R01 A1064826-01, U19 AI062627-01, NO1-HHSN26600500032C]
- [RSG CCG-106204]
- [R01 AI52327]
- [R01 HL073284]
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.
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