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.

In the work presented above, the interplay between cytokines and intracellular signaling molecules in the regulation of NK cell activation and function is defined at the earliest site of viral infection in immunocompetent mice. Production of IFN-␣, IFN-␤, and IFN-␥ in the peritoneal cavity was shown to peak at 30 h after LCMV infection. NK cells were the major producers of IFN-␥ and uniquely expressed high levels of STAT4. The pathway for induction of NK cell IFN-␥ production was dependent on responsiveness to type 1 IFNs and on the STAT4 signaling molecule. The elicited IFN-␥ enhanced defense because loss of responsiveness to the factor resulted in increased viral burdens. Thus, type 1 IFN induction of IFN-␥ production by NK cells, dependent on STAT4, is conclusively proven to occur and to lead to downstream effects under immunocompetent conditions. Previous work from this laboratory has established that under basal conditions, splenic NK cells express high STAT4 and low STAT1 levels and preferentially activate STAT4 over STAT1 after ex vivo exposure to type 1 IFNs (9). Nevertheless, it has only been possible to identify type 1 IFN activation of STAT4 and IFN-␥ in the spleens of STAT1-deficient mice during LCMV infection because the type 1 IFNs and IFN-␥ induce STAT1 levels to block the pathway to STAT4 (9). The results reported here answer the question of why a pathway from type 1 IFN to STAT4 for IFN-␥ expression would be maintained when it is rapidly turned off by concurrent STAT1 induction; it is used to locally access a short burst of IFN-␥ at very early times after infection. In this case, "locally" is the peritoneal cavity. In addition to the detectable NK cell IFN-␥ response, innate responses to LCMV at this site differed from the well-characterized responses in spleen and serum (7, 9, 17) with regard to the kinetics and magnitude of type 1 IFN production and the kinetics of STAT1 induction in NK cells (9) . Type 1 IFN production in the peritoneal cavity was very early and of short duration-detectable at 24 h, peaking at 30 h, and resolving by 36 h after infection (Fig. 1 )-and although total lymphocytes and T cells had dramatically elevated STAT1 levels early, induction was delayed by 8 to 16 h in the NK cells (Fig. 5) . Thus, in contrast to the spleen, the environment in the peritoneal cavity allows type 1 IFN to access STAT4 prior to STAT1 induction in NK cells (Fig. 7) .