1. ¹Laboratory of Molecular Immunology, Blood Research Institute, Milwaukee, WI, USA
2. ²Receptor Signaling Laboratory, Blood Research Institute, Milwaukee, WI, USA
3. ³Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI, USA
4. ⁴Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA

Correspondence: Dr S Malarkannan, Laboratory of Molecular Immunology, Blood Research Institute, 8727 Watertown Plank Road, Milwaukee, WI 53226, USA. E-mail: subra.malar@bcw.edu

Received 6 March 2008; Revised 12 May 2008; Accepted 12 May 2008; Published online 12 June 2008.

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 p85 subunit and its alternatively spliced variants p55/p50 (collectively termed as p85^-/-), we defined the role of PI3K in NK cell development and function. p85^-/- mice had impaired lineage commitment leading to reduced NK cellularity in the bone marrow and liver. p85^-/- NK cells showed a defective Ly49 subset specification and a decreased expression of CD43. Lack of p85 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^-/- NK cells. These results reveal a previously unrecognized role of p85 in the development, terminal maturation, cytokine/chemokine generation and tumor clearance of NK cells.