Acquisition of Murine NK Cell Cytotoxicity Requires the Translation of a Pre-existing Pool of Granzyme B and Perforin mRNAs

Todd A. Fehniger; Sheng F. Cai; Xuefang Cao; Andrew J. Bredemeyer; Rachel M. Presti; Anthony R R. French; Timothy J. Ley

doi:10.1016/j.immuni.2007.04.010

Acquisition of Murine NK Cell Cytotoxicity Requires the Translation of a Pre-existing Pool of Granzyme B and Perforin mRNAs

Todd A. Fehniger, Sheng F. Cai, Xuefang Cao, Andrew J. Bredemeyer, Rachel M. Presti, Anthony R R. French, Timothy J. Ley

Research output: Contribution to journal › Article › peer-review

354 Scopus citations

Abstract

Although activated murine NK cells can use the granule exocytosis pathway to kill target cells immediately upon recognition, resting murine NK cells are minimally cytotoxic for unknown reasons. Here, we showed that resting NK cells contained abundant granzyme A, but little granzyme B or perforin; in contrast, the mRNAs for all three genes were abundant. Cytokine-induced in vitro activation of NK cells resulted in potent cytotoxicity associated with a dramatic increase in granzyme B and perforin, but only minimal changes in mRNA abundance for these genes. The same pattern of regulation was found in vivo with murine cytomegalovirus infection as a physiologic model of NK cell activation. These data suggest that resting murine NK cells are minimally cytotoxic because of a block in perforin and granzyme B mRNA translation that is released by NK cell activation.

Original language	English
Pages (from-to)	798-811
Number of pages	14
Journal	Immunity
Volume	26
Issue number	6
DOIs	https://doi.org/10.1016/j.immuni.2007.04.010
State	Published - Jun 22 2007

Keywords

CELLIMMUNO
MOLIMMUNO

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10.1016/j.immuni.2007.04.010

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title = "Acquisition of Murine NK Cell Cytotoxicity Requires the Translation of a Pre-existing Pool of Granzyme B and Perforin mRNAs",

abstract = "Although activated murine NK cells can use the granule exocytosis pathway to kill target cells immediately upon recognition, resting murine NK cells are minimally cytotoxic for unknown reasons. Here, we showed that resting NK cells contained abundant granzyme A, but little granzyme B or perforin; in contrast, the mRNAs for all three genes were abundant. Cytokine-induced in vitro activation of NK cells resulted in potent cytotoxicity associated with a dramatic increase in granzyme B and perforin, but only minimal changes in mRNA abundance for these genes. The same pattern of regulation was found in vivo with murine cytomegalovirus infection as a physiologic model of NK cell activation. These data suggest that resting murine NK cells are minimally cytotoxic because of a block in perforin and granzyme B mRNA translation that is released by NK cell activation.",

keywords = "CELLIMMUNO, MOLIMMUNO",

author = "Fehniger, {Todd A.} and Cai, {Sheng F.} and Xuefang Cao and Bredemeyer, {Andrew J.} and Presti, {Rachel M.} and French, {Anthony R R.} and Ley, {Timothy J.}",

note = "Funding Information: This work was supported by grants by the National Institutes of Health (DK49786 to T.J.L., AI059083 to A.R.F.). We thank the Hi Speed Flow Core, the Multiplexed Gene Analysis Core, and the Bioinformatics Core of Siteman Cancer Center for their invaluable support. M. Hoock provided excellent animal husbandry, and M. Hapak provided outstanding assistance with Cr-release assays. We thank M. Cooper, B. Carreno, J. Payton, D. Link, and T. Graubert for insightful discussions. The Gzma mAb was developed in part with the WUSM Hybridoma Center (supported by the Department of Pathology and Immunology and NIH grant P30 AR048335). T.J.L. holds the license for the Gzma monoclonal antibody clone 3G8.5 (Santa Cruz). The authors have no other special/competing interests to disclose. ",

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doi = "10.1016/j.immuni.2007.04.010",

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T1 - Acquisition of Murine NK Cell Cytotoxicity Requires the Translation of a Pre-existing Pool of Granzyme B and Perforin mRNAs

AU - Fehniger, Todd A.

AU - Cai, Sheng F.

AU - Cao, Xuefang

AU - Bredemeyer, Andrew J.

AU - Presti, Rachel M.

AU - French, Anthony R R.

AU - Ley, Timothy J.

N1 - Funding Information: This work was supported by grants by the National Institutes of Health (DK49786 to T.J.L., AI059083 to A.R.F.). We thank the Hi Speed Flow Core, the Multiplexed Gene Analysis Core, and the Bioinformatics Core of Siteman Cancer Center for their invaluable support. M. Hoock provided excellent animal husbandry, and M. Hapak provided outstanding assistance with Cr-release assays. We thank M. Cooper, B. Carreno, J. Payton, D. Link, and T. Graubert for insightful discussions. The Gzma mAb was developed in part with the WUSM Hybridoma Center (supported by the Department of Pathology and Immunology and NIH grant P30 AR048335). T.J.L. holds the license for the Gzma monoclonal antibody clone 3G8.5 (Santa Cruz). The authors have no other special/competing interests to disclose.

PY - 2007/6/22

Y1 - 2007/6/22

N2 - Although activated murine NK cells can use the granule exocytosis pathway to kill target cells immediately upon recognition, resting murine NK cells are minimally cytotoxic for unknown reasons. Here, we showed that resting NK cells contained abundant granzyme A, but little granzyme B or perforin; in contrast, the mRNAs for all three genes were abundant. Cytokine-induced in vitro activation of NK cells resulted in potent cytotoxicity associated with a dramatic increase in granzyme B and perforin, but only minimal changes in mRNA abundance for these genes. The same pattern of regulation was found in vivo with murine cytomegalovirus infection as a physiologic model of NK cell activation. These data suggest that resting murine NK cells are minimally cytotoxic because of a block in perforin and granzyme B mRNA translation that is released by NK cell activation.

AB - Although activated murine NK cells can use the granule exocytosis pathway to kill target cells immediately upon recognition, resting murine NK cells are minimally cytotoxic for unknown reasons. Here, we showed that resting NK cells contained abundant granzyme A, but little granzyme B or perforin; in contrast, the mRNAs for all three genes were abundant. Cytokine-induced in vitro activation of NK cells resulted in potent cytotoxicity associated with a dramatic increase in granzyme B and perforin, but only minimal changes in mRNA abundance for these genes. The same pattern of regulation was found in vivo with murine cytomegalovirus infection as a physiologic model of NK cell activation. These data suggest that resting murine NK cells are minimally cytotoxic because of a block in perforin and granzyme B mRNA translation that is released by NK cell activation.

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Acquisition of Murine NK Cell Cytotoxicity Requires the Translation of a Pre-existing Pool of Granzyme B and Perforin mRNAs

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