title: The p110 delta of PI3K plays a critical role in NK cell terminal maturation and cytokine/chemokine generation.
abstract: 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 delta(D910A), a catalytically inactive p110 delta, we show that these mice had reduced NK cellularity, defective Ly49C and Ly49I NK subset maturation, and decreased CD27(High) NK numbers. p110 delta 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 delta(D910A/D910A) NK cell-mediated antiviral responses through natural cytotoxicity receptor 1 were reduced. Analysis of signaling events demonstrates that p110 delta(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 delta in NK cell development and effector functions.
authors.affiliation: Laboratory of Molecular Immunology, Blood Research Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Hailong
authors.initials: H
authors.lastname: Guo
authors.forename: Asanga
authors.initials: A
authors.lastname: Samarakoon
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Malarkannan
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation; D018925:Chemokines / Q000276:immunology*; D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines / Q000276:immunology*; D006801:Humans; D009980:Influenza A virus / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000502:physiology*; D037181:Lectins, C-Type / Q000276:immunology; D016131:Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D055650:NK Cell Lectin-Like Receptor Subfamily A; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D055630:Receptors, NK Cell Lectin-Like; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000950:Antigens, Ly; D018925:Chemokines; D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines; D007371:Interferon-gamma; D037181:Lectins, C-Type; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D055650:NK Cell Lectin-Like Receptor Subfamily A; D019869:Phosphatidylinositol 3-Kinases; D021122:Protein Subunits; D055630:Receptors, NK Cell Lectin-Like; C527091:Klra3 protein, mouse; C527092:Klra4 protein, mouse; C421683:Pik3cd protein, mouse