Acquisition of murine NK cell cytotoxicity requires the translation of a pre-existing pool of granzyme B and perforin mRNAs.
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.
Fehniger
Todd A
TA
Division of Oncology, Department of Internal Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
Cai
Sheng F
SF
Cao
Xuefang
X
Bredemeyer
Andrew J
AJ
Presti
Rachel M
RM
French
Anthony R
AR
Ley
Timothy J
TJ
D000818:Animals; D016207:Cytokines / Q000494:pharmacology; D003586:Cytomegalovirus Infections / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D053804:Granzymes / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D019409:Interleukin-15 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008817:Mice, Mutant Strains; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D022142:Secretory Vesicles / Q000378:metabolism
D016207:Cytokines; D019409:Interleukin-15; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger; C510467:perforin 1, mouse; D054353:Perforin; D053804:Granzymes