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The p110 of PI3K plays a critical role in NK cell terminal maturation and cytokine/chemokine generation

¹ Laboratory of Molecular Immunology, Blood Research Institute and ² Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226
³ Centre for Cell Signaling, Institute of Cancer, Queen Mary, University of London, Charterhouse Square, London EC1M 6BQ, England, UK

CORRESPONDENCE Subramaniam Malarkannan: subra.malar{at}bcw.edu

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^D910A, a catalytically inactive p110, we show that these mice had reduced NK cellularity, defective Ly49C and Ly49I NK subset maturation, and decreased CD27^High NK numbers. p110 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^D910A/D910A NK cell–mediated antiviral responses through natural cytotoxicity receptor 1 were reduced. Analysis of signaling events demonstrates that p110^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 in NK cell development and effector functions.

© 2008 Guo et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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