title: Distinct requirements for IFNs and STAT1 in NK cell function.
abstract: NK cell functions were examined in mice with a targeted mutation of the STAT1 gene, an essential mediator of IFN signaling. Mice deficient in STAT1 displayed impaired basal NK cytolytic activity in vitro and were unable to reject transplanted tumors in vivo, despite the presence of normal numbers of NK cells. IL-12 enhanced NK-mediated cytolysis, but poly(I:C) did not, and a similar phenotype occurred in mice lacking IFNalpha receptors. Molecules involved in activation and lytic function of NK cells (granzyme A, granzyme B, perforin, DAP10, and DAP12) were expressed at comparable levels in both wild-type and STAT1(-/-) mice, and serine esterase activity necessary for CTL function was normal, showing that the lytic machinery was intact. NK cells with normal cytolytic activity could be derived from STAT1(-/-) bone marrow progenitors in response to IL-15 in vitro, and enhanced NK lytic activity and normal levels of IFN-gamma were produced in response to IL-12 treatment in vivo. Despite these normal responses to cytokines, STAT1(-/-) mice could not reject the NK-sensitive tumor RMA-S, even following IL-12 treatment in vivo. Whereas in vitro NK cytolysis was also reduced in mice lacking both type I and type II IFN receptors, these mice resisted tumor challenge. These results demonstrate that both IFN-alpha and IFN-gamma are required to maintain NK cell function and define a STAT1-dependent but partially IFN-independent pathway required for NK-mediated antitumor activity.
authors.affiliation: Department of Pathology, Kaplan Comprehensive Cancer Center, New York University School of Medicine, NY 10016, USA.
authors.forename: C K
authors.initials: CK
authors.lastname: Lee
authors.forename: D T
authors.initials: DT
authors.lastname: Rao
authors.forename: R
authors.initials: R
authors.lastname: Gertner
authors.forename: R
authors.initials: R
authors.lastname: Gimeno
authors.forename: A B
authors.initials: AB
authors.lastname: Frey
authors.forename: D E
authors.initials: DE
authors.lastname: Levy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D053804:Granzymes; D007371:Interferon-gamma / Q000502:physiology; D007372:Interferons / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018664:Interleukin-12 / Q000502:physiology; D019409:Interleukin-15 / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011971:Receptors, Immunologic / Q000096:biosynthesis; D050794:STAT1 Transcription Factor; D012697:Serine Endopeptidases / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C492355:Hcst protein, mouse; D019409:Interleukin-15; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D052899:Pore Forming Cytotoxic Proteins; D011971:Receptors, Immunologic; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C110546:TYROBP protein, human; D015534:Trans-Activators; D054353:Perforin; D018664:Interleukin-12; D007371:Interferon-gamma; D007372:Interferons; C509213:GZMB protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases; C509212:GZMA protein, human