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J Immunol. 2015 Feb 15;194(4):1832-40. doi: 10.4049/jimmunol.1401224. Epub 2015 Jan 16.

PTEN is a negative regulator of NK cell cytolytic function.

Author information

1
Medical Scientist Training Program and Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210;
2
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;
3
The Comprehensive Cancer Center and Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210;
4
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;
5
Center for Human Immunobiology, Baylor College of Medicine Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030;
6
The Molecular, Cellular, and Developmental Biology Program, The Ohio State University, Columbus, OH 43210;
7
Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
8
Center for Biostatistics, The Ohio State University, Columbus, OH 43210;
9
Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210;
10
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;
11
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.
12
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;
13
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210.
14
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.

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.

PMID:
25595786
PMCID:
PMC4319309
DOI:
10.4049/jimmunol.1401224
[Indexed for MEDLINE]
Free PMC Article

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