TY - JOUR
T1 - PTEN is a negative regulator of NK cell cytolytic function
AU - Briercheck, Edward L.
AU - Trotta, Rossana
AU - Chen, Li
AU - Hartlage, Alex S.
AU - Cole, Jordan P.
AU - Cole, Tyler D.
AU - Mao, Charlene
AU - Banerjee, Pinaki P.
AU - Hsu, Hsiang Ting
AU - Mace, Emily M.
AU - Ciarlariello, David
AU - Mundy-Bosse, Bethany L.
AU - Garcia-Cao, Isabel
AU - Scoville, Steven D.
AU - Yu, Lianbo
AU - Pilarski, Robert
AU - Carson, William E.
AU - Leone, Gustavo
AU - Pandolfi, Pier Paolo
AU - Yu, Jianhua
AU - Orange, Jordan S.
AU - Caligiuri, Michael A.
N1 - Publisher Copyright:
Copyright © 2015 by The American Association of Immunologists, Inc.
PY - 2015/2/15
Y1 - 2015/2/15
N2 - 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 CD56dim NK cell efficiently kills malignant targets at rest, whereas the less mature CD56bright NK cells cannot. In this study, we show that resting CD56bright NK cells express significantly more phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein when compared with CD56dim NK cells. Consistent with this, forced overexpression of PTEN in NK cells resulted in decreased cytolytic activity, and loss of PTEN in CD56bright 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 CD56bright NK cell to the cytolytic CD56dim NK cells.
AB - 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 CD56dim NK cell efficiently kills malignant targets at rest, whereas the less mature CD56bright NK cells cannot. In this study, we show that resting CD56bright NK cells express significantly more phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein when compared with CD56dim NK cells. Consistent with this, forced overexpression of PTEN in NK cells resulted in decreased cytolytic activity, and loss of PTEN in CD56bright 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 CD56bright NK cell to the cytolytic CD56dim NK cells.
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U2 - 10.4049/jimmunol.1401224
DO - 10.4049/jimmunol.1401224
M3 - Article
C2 - 25595786
AN - SCOPUS:84922569775
SN - 0022-1767
VL - 194
SP - 1832
EP - 1840
JO - Journal of Immunology
JF - Journal of Immunology
IS - 4
ER -