title: PI3K p85 β regulatory subunit deficiency does not affect NK cell differentiation and increases NKG2D-mediated activation.
abstract: Activation of NK cells depends on a balance between activating and inhibitory signals. Class Ia PI3K are heterodimeric proteins with a catalytic and a regulatory subunit and have a central role in cell signaling by associating with tyrosine kinase receptors to trigger signaling cascades. The regulatory p85 subunit participates in signaling through NKG2D, one of the main activating receptors on NK cells, via its interaction with the adaptor protein DAP10. Although the effects of inhibiting catalytic subunits or deleting the regulatory p85α subunit have been studied, little attention has focused on the role of the p85β subunit in NK cells. Using p85β knockout mice, we found that p85β deficiency does not alter NK cell differentiation and maturation in spleen or bone marrow. NK cells from p85β-/-mice nonetheless produced more IFN-γ and degranulated more effectively when stimulated with anti-NKG2D antibody. These cells also degranulated and killed NKG2D ligand-expressing target cells more efficiently. We show that p85β deficiency impaired NKG2D internalization, which could contribute to the activated phenotype. Decreasing p85β subunit protein levels might thus constitute a therapeutic target to promote NK cell activity toward NKG2D ligand-expressing cells.
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Rojas
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: Spada
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Sanz-Ortega
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Morillas
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Mejías
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Mulens-Arias
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Pérez-Yagüe
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain dfbarber@cnb.csic.es.
authors.forename: Domingo F
authors.initials: DF
authors.lastname: Barber
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000276:immunology; D015550:Cell Degranulation; D002478:Cells, Cultured; D015536:Down-Regulation; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000166:cytology*; D008213:Lymphocyte Activation; D038041:Lymphopoiesis; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D021122:Protein Subunits; D011971:Receptors, Immunologic / Q000276:immunology; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000166:cytology / Q000276:immunology
chemical_list: C492355:Hcst protein, mouse; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D021122:Protein Subunits; D011971:Receptors, Immunologic; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; C000622311:phosphoinositol-3 kinase regulatory subunit 2, mouse
keywords: Cbl; DAP10; IFN-γ; degranulation; phosphoinositide-3-kinase