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Deletion of PI3K-p85α gene impairs lineage commitment, terminal maturation, cytokine generation and cytotoxicity of NK cells

Genes & Immunity volume 9, pages 522–535 (2008)Cite this article

Abstract

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 p85α subunit and its alternatively spliced variants p55α/p50α (collectively termed as p85α−/−), we defined the role of PI3K in NK cell development and function. p85α−/− mice had impaired lineage commitment leading to reduced NK cellularity in the bone marrow and liver. p85α−/− NK cells showed a defective Ly49 subset specification and a decreased expression of CD43. Lack of p85α 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 p85α−/− NK cells. These results reveal a previously unrecognized role of p85α in the development, terminal maturation, cytokine/chemokine generation and tumor clearance of NK cells.

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Acknowledgements

We thank David A Fruman and Lewis C Cantley for p85α–/– mice. This work was supported in part by ACS Scholar grants RSG-02-172-LIB (to SM); RSG CCG-106204 (to DW); ROTRF grant no. 111662730 (to SM); and NIH grants R01 A1064826-01, U19 AI062627-01, NO1-HHSN26600500032C (to SM); R01 AI52327 (to RW) and R01 HL073284 (to DW).

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  1. Laboratory of Molecular Immunology, Blood Research Institute, Milwaukee, WI, USA

    A Awasthi, A Samarakoon & S Malarkannan

  2. Receptor Signaling Laboratory, Blood Research Institute, Milwaukee, WI, USA

    X Dai, R Wen & D Wang

  3. Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI, USA

    D Wang & S Malarkannan

  4. Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA

    S Malarkannan

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  1. A Awasthi
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Correspondence to S Malarkannan.

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Awasthi, A., Samarakoon, A., Dai, X. et al. Deletion of PI3K-p85α gene impairs lineage commitment, terminal maturation, cytokine generation and cytotoxicity of NK cells. Genes Immun 9, 522–535 (2008). https://doi.org/10.1038/gene.2008.45

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