Year: 2015
Type: article
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.
Source: The Journal of Immunology
Authors: Edward L Briercheck, Rossana Trotta, Li Chen, Alex S Hartlage, Jordan P Cole, Tyler D Cole, Charlene Mao, Pinaki P Banerjee, Hsiang-Ting Hsu, Emily M Mace, David Ciarlariello, Bethany L Mundy-Bosse, Isabel Garcia-Cao, Steven D Scoville, Lianbo Yu, Robert Pilarski, William E Carson, Gustavo Leone, Pier Paolo Pandolfi, Jianhua Yu, Jordan S Orange, Michael A Caligiuri
Institutions: The Ohio State University, University of Maryland, Baltimore, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital, Beth Israel Deaconess Medical Center, Harvard University
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
Awards: Innate Immunity: Elucidation and Modulation for Cancer Therapy, The role of the aryl hydrocarbon receptor in natural killer cell development in normal and acute myeloid leukemia donors, IL-15 characterization through experimental immunology, G2714647962, Oncology Training Grant, G376373994, G3961235898, IL-15 Characterization Through Experimental Immunology, Genetic Analysis of the Breast Tumor Microenvironment, G9000085958, G9000218012, Directing Function at the Natural Killer Cell Secretory Immunological Synapse, Cancer Center Support Grant
OpenAlex ID: W2108093831