Type 1 Interferon Induction of Natural Killer Cell Gamma Interferon Production for Defense during Lymphocytic Choriomeningitis Virus Infection

Mack, Ethan A.; Kallal, Lara E.; Demers, Delia A.; Biron, Christine A.

The studies do not exclude possible roles for accessory cytokines in enhancing type 1 IFN induction of IFN-␥. Certainly, IL-12 is an activator of STAT4 and a potent inducer of IFN-␥ (13, 34) . The cytokine IL-18 can enhance the stimulation of IFN-␥ by either type 1 IFNs or IL-12 (7, (35) (36) (37) , and new studies deciphering pathways from different sensors have demonstrated synergism between type 1 IFNs and IL-12 for IFN-␥ induction in human cells (38) . The results presented here, however, suggest that there may be a short burst of IFN-␥ induced by type 1 IFNs independent of IL-12, and our previous work examining murine cytomegalovirus infections of mice has shown that induced type 1 IFNs promote NK cell cytotoxicity but IL-12 is required for splenic and systemic NK cell IFN-␥ (3, 4) . The experiments carried out here neutralizing IL-12 in vivo show that IL-12 does not play a role in the LCMVinduced NK cell IFN-␥ response (Fig. 2) . Interestingly, the positive controls for these studies (i.e., effects on LPS induction of IFN-␥ in the peritoneal cavity) (Fig. 2) demonstrate that when it is elicited, IL-12 is important in eliciting a peritoneal NK cell IFN-␥, but also that there is residual NK cell IFN-␥ after neutralization. This is consistent with early reports of incomplete IFN-␥ blockade by IL-12 neutralization following LPS treatment in other settings (21) and the known LPS induction of IFN-␤ (39) . Taken together, the studies suggest that IL-12 is an important inducer of NK cell IFN-␥ if elicited and the critical cytokine for IFN-␥ induction once STAT1 levels are increased. There are likely to be additional regulatory factors in play, however, as the presence of STAT1 eventually results in reduced IFN-␥ induction by either type 1 IFNs or IL-12 (6) . Thus, much remains to be done to map the complex interactions between type 1 IFN and IL-12 for shaping NK cell responses, but eliciting different type 1 IFN and IL-12 responses may be part of directing the magnitude of, and continued access to, the NK cell IFN-␥ response.