Deletion of PI3K-p85alpha gene impairs lineage commitment, terminal maturation, cytokine generation and cytotoxicity of NK cells.
Class IA phosphotidylinositol-3-kinases (PI3Ks) are a family of p85/p110 heterodimeric lipid kinases that are important in regulating signaling events in B and T cells. However, their role in natural killer (NK) cells is not understood. Here, using mice that lack the regulatory p85alpha subunit and its alternatively spliced variants p55alpha/p50alpha (collectively termed as p85alpha(-/-)), we defined the role of PI3K in NK cell development and function. p85alpha(-/-) mice had impaired lineage commitment leading to reduced NK cellularity in the bone marrow and liver. p85alpha(-/-) NK cells showed a defective Ly49 subset specification and a decreased expression of CD43. Lack of p85alpha severely reduced the NK-mediated cytotoxicity against tumor cells representing 'induced-self' and 'missing-self'. More importantly, NKG2D and NK1.1 receptor-mediated cytokine and chemokine generation was significantly compromised in p85alpha(-/-) NK cells. These results reveal a previously unrecognized role of p85alpha in the development, terminal maturation, cytokine/chemokine generation and tumor clearance of NK cells.
Awasthi
A
A
Laboratory of Molecular Immunology, Blood Research Institute, Milwaukee, WI, USA.
Samarakoon
A
A
Dai
X
X
Wen
R
R
Wang
D
D
Malarkannan
S
S
D000818:Animals; D001853:Bone Marrow / Q000276:immunology; D002454:Cell Differentiation; D018925:Chemokines / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D039564:Integrin alphaV / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology* / Q000276:immunology*; D051917:Leukosialin / Q000276:immunology; D008099:Liver / Q000276:immunology; D051379:Mice; D055655:NK Cell Lectin-Like Receptor Subfamily K; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology; D055607:Receptors, Natural Killer Cell
D018925:Chemokines; D016207:Cytokines; D039564:Integrin alphaV; C527086:Klrk1 protein, mouse; D051917:Leukosialin; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D019869:Phosphatidylinositol 3-Kinases