title: The p110delta catalytic isoform of PI3K is a key player in NK-cell development and cytokine secretion.
abstract: 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 p110delta, not p110gamma, 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 p110delta and p110gamma isoforms were inactivated by a combination of genetic and biochemical approaches, cytotoxicity was decreased. NK-cell numbers were also affected by the lack of p110delta but not p110gamma and more severely so in mice lacking both subunits. These results provide genetic evidence that p110delta is the dominant PI3K isoform for cytokine secretion by NK cells and suggest that PI3Ks cooperate during NK-cell development and cytotoxicity.
authors.affiliation: Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom.
authors.forename: Nayoung
authors.initials: N
authors.lastname: Kim
authors.forename: Aurore
authors.initials: A
authors.lastname: Saudemont
authors.forename: Louise
authors.initials: L
authors.lastname: Webb
authors.forename: Montserrat
authors.initials: M
authors.lastname: Camps
authors.forename: Thomas
authors.initials: T
authors.lastname: Ruckle
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: Martin
authors.initials: M
authors.lastname: Turner
authors.forename: Francesco
authors.initials: F
authors.lastname: Colucci
mesh_terms: D000818:Animals; D020134:Catalytic Domain / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D005260:Female; D007694:Killer Cells, Natural / Q000166:cytology* / Q000378:metabolism*; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology*; D020033:Protein Isoforms / Q000502:physiology; D011956:Receptors, Cell Surface / Q000378:metabolism
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines; D019869:Phosphatidylinositol 3-Kinases; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; C421683:Pik3cd protein, mouse