title: PTEN is a negative regulator of NK cell cytolytic function.
abstract: Human NK cells are characterized by their ability to initiate an immediate and direct cytolytic response to virally infected or malignantly transformed cells. Within human peripheral blood, the more mature CD56(dim) NK cell efficiently kills malignant targets at rest, whereas the less mature CD56(bright) NK cells cannot. In this study, we show that resting CD56(bright) NK cells express significantly more phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein when compared with CD56(dim) NK cells. Consistent with this, forced overexpression of PTEN in NK cells resulted in decreased cytolytic activity, and loss of PTEN in CD56(bright) NK cells resulted in elevated cytolytic activity. Comparable studies in mice showed PTEN overexpression did not alter NK cell development or NK cell-activating and inhibitory receptor expression yet, as in humans, did decrease expression of downstream NK activation targets MAPK and AKT during early cytolysis of tumor target cells. Confocal microscopy revealed that PTEN overexpression disrupts the NK cell's ability to organize immunological synapse components including decreases in actin accumulation, polarization of the microtubule organizing center, and the convergence of cytolytic granules. In summary, our data suggest that PTEN normally works to limit the NK cell's PI3K/AKT and MAPK pathway activation and the consequent mobilization of cytolytic mediators toward the target cell and suggest that PTEN is among the active regulatory components prior to human NK cells transitioning from the noncytolytic CD56(bright) NK cell to the cytolytic CD56(dim) NK cells.
authors.affiliation: Medical Scientist Training Program and Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210;
authors.forename: Edward L
authors.initials: EL
authors.lastname: Briercheck
authors.affiliation: The Comprehensive Cancer Center and Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210; Department of Microbiology and Immunology and Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201;
authors.forename: Rossana
authors.initials: R
authors.lastname: Trotta
authors.affiliation: The Comprehensive Cancer Center and Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210;
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Medical Scientist Training Program and Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210;
authors.forename: Alex S
authors.initials: AS
authors.lastname: Hartlage
authors.affiliation: The Comprehensive Cancer Center and Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210;
authors.forename: Jordan P
authors.initials: JP
authors.lastname: Cole
authors.affiliation: The Comprehensive Cancer Center and Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210;
authors.forename: Tyler D
authors.initials: TD
authors.lastname: Cole
authors.affiliation: The Comprehensive Cancer Center and Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210;
authors.forename: Charlene
authors.initials: C
authors.lastname: Mao
authors.affiliation: Center for Human Immunobiology, Baylor College of Medicine Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030; Department of Pediatrics, Baylor College of Medicine Texas Children's Hospital, Houston, TX 77030;
authors.forename: Pinaki P
authors.initials: PP
authors.lastname: Banerjee
authors.affiliation: Center for Human Immunobiology, Baylor College of Medicine Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Hsiang-Ting
authors.initials: HT
authors.lastname: Hsu
authors.affiliation: Center for Human Immunobiology, Baylor College of Medicine Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Emily M
authors.initials: EM
authors.lastname: Mace
authors.affiliation: The Molecular, Cellular, and Developmental Biology Program, The Ohio State University, Columbus, OH 43210;
authors.forename: David
authors.initials: D
authors.lastname: Ciarlariello
authors.affiliation: The Comprehensive Cancer Center and Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210;
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Mundy-Bosse
authors.affiliation: Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Isabel
authors.initials: I
authors.lastname: Garcia-Cao
authors.affiliation: Medical Scientist Training Program and Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210;
authors.forename: Steven D
authors.initials: SD
authors.lastname: Scoville
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, OH 43210;
authors.forename: Lianbo
authors.initials: L
authors.lastname: Yu
authors.affiliation: Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210;
authors.forename: Robert
authors.initials: R
authors.lastname: Pilarski
authors.affiliation: Medical Scientist Training Program and Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210; The Comprehensive Cancer Center and Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210; Department of Surgery, The Ohio State University, Columbus, OH 43210;
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
authors.affiliation: Medical Scientist Training Program and Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210; The Comprehensive Cancer Center and Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210; Department of Molecular Genetics, The Ohio State University, Columbus, OH 43210; Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210; and.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Leone
authors.affiliation: The Molecular, Cellular, and Developmental Biology Program, The Ohio State University, Columbus, OH 43210; Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.affiliation: Center for Human Immunobiology, Baylor College of Medicine Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030; Department of Pediatrics, Baylor College of Medicine Texas Children's Hospital, Houston, TX 77030;
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.affiliation: Medical Scientist Training Program and Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210; The Comprehensive Cancer Center and Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210; Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210; and Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D051059:PTEN Phosphohydrolase / Q000276:immunology* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D051059:PTEN Phosphohydrolase