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The Journal of Immunology, 2000, 165: 3571-3577.
Copyright © 2000 by The American Association of Immunologists

Distinct Requirements for IFNs and STAT1 in NK Cell Function1

Chien-Kuo Lee2,*, Dharma T. Rao{dagger}, Rachel Gertner*, Ramon Gimeno*, Alan B. Frey{dagger} and David E. Levy3,*

Departments of * Pathology and {dagger} Cell Biology, Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, NY 10016

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 IFN{alpha} 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.




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