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 Blood, 1 November 2007, Vol. 110, No. 9, pp. 3202-3208.
Prepublished online as a Blood First Edition Paper on July 20, 2007; DOI 10.1182/blood-2007-02-075366.

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IMMUNOBIOLOGY

The p110delta catalytic isoform of PI3K is a key player in NK-cell development and cytokine secretion

Nayoung Kim1, Aurore Saudemont1, Louise Webb1, Montserrat Camps2, Thomas Ruckle2, Emilio Hirsch3, Martin Turner1, and Francesco Colucci1

1 Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom; 2 Merck Serono Research Centre, Merck Serono, Geneva, Switzerland; and 3 Dipartimento di Genetica, Biologia e Biochimica, Centre for Molecular Biotechnology, Torino, Italy

The signal transduction pathways that lead activated natural killer (NK) cells to produce cytokines, releases cytotoxic granules, or do both, are not clearly dissected. For example, phosphoinositide 3-kinases (PI3Ks) are key players in the execution of both functions, but the relative contribution of each isoform is unknown. We show here that the catalytic isoform p110{delta}, not p110{gamma}, was required for interferon-{gamma} (IFN-{gamma}), tumor necrosis factor-{alpha} (TNF-{alpha}), and granulocyte macrophage colony-stimulating factor (GM-CSF) secretion, whereas neither was necessary for cytotoxicity. Yet, when both p110{delta} and p110{gamma} isoforms were inactivated by a combination of genetic and biochemical approaches, cytotoxicity was decreased. NK-cell numbers were also affected by the lack of p110{delta} but not p110{gamma} and more severely so in mice lacking both subunits. These results provide genetic evidence that p110{delta} is the dominant PI3K isoform for cytokine secretion by NK cells and suggest that PI3Ks cooperate during NK-cell development and cytotoxicity.


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