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.

have early access to STAT4 and the NK cell IFN-␥ pathway prior to STAT1 induction and that this pathway promotes resistance to infection. Recent studies have shown that similar STAT4-STAT1 regulation is in place in humans; type 1 IFNs induce STAT4 activation in NK cells isolated from healthy individuals, but the response is diminished in NK cells from individuals chronically infected with hepatitis C virus. The activation of STAT4 negatively correlates with STAT1 levels in these populations (29) . Thus, modulation of STAT4 and STAT1 concentrations in different cell types under different conditions of infections in mice and humans helps explain how type 1 IFNs can enhance or antagonize IFN-␥ stimulation, and the studies with mice provide explanations for how the balance, in both directions, works to the benefit of the host. A change in relative STAT ratios might also play a role in conditioning NK cells to modify type 1 IFN responses from promoting cytokine production to enhancing cytotoxic function. In addition to our earlier studies with STAT1-deficient mice, there have been a few other reports suggesting a role of type 1 IFN in NK cell IFN-␥ expression. One examined a number of activation responses, including intracellular IFN-␥, of type 1 IFN receptor-deficient compared to WT NK cells following in vitro exposure to vaccinia virus and dendritic cells (30) . Early in vivo IFN-␥ induction has been reported in the mouse peritoneum during different viral infections (31) , and intracellular IFN-␥ expression by splenic NK cells has been observed following treatments with the chemical analogue of viral nucleic acids, polyinosinicpolycytidylic acid [poly(I · C)] (32, 33) . These in vivo studies, however, have been done under conditions where the type 1 IFN effects were not delineated from those that might have been mediated by other cytokines induced under the experimental conditions used, including reported IL-12. In one study with poly(I · C) (32), the intracellular NK cell IFN-␥ expression was shown to be blocked by treatments with antibodies neutralizing type 1 IFN function, but the consequences of the treatments on other cytokine responses were not evaluated. Here, in vivo responses under which the type 1 IFN receptor was blocked were evaluated by different approaches, including adoptive transfer of peritoneal populations from WT or type 1 IFN receptor-deficient mice into WT-infected mice (Fig. 3) . This method allows direct comparison of donor and recipient cells in the context of the complete endogenous immune responses. Thus, to our knowledge, this is the first demonstration of type 1 IFNs inducing IFN-␥ production from NK cells under immunocompetent conditions of viral infection.