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.

Our studies are helping to resolve conflicting reports in the literature on potential type 1 IFN consequences for IFN-␥ expression (5, 6, 9) , adding information to the growing literature reporting cellular differences in type 1 IFN responses (27, 28) and advancing the mechanistic understanding of how the biological effects of STAT cytokines are regulated to access diverse and paradoxical effects as needed. Type 1 IFNs have long been known to exert antiviral effects and enhance NK cell cytotoxicity through the activation of STAT1 (4, 5, 11) . The NK cells, however, are positioned to respond to type 1 IFNs with STAT4 activation because high basal levels of STAT4 are associated with the type 1 IFN receptor (9) . Increasing the endogenous levels of total STAT1 protein negatively regulates STAT4 access in part by displacing STAT4 from the receptor, and this induction of STAT1, as observed in the spleen, is beneficial because it protects from dysregulated systemic IFN-␥ production and cytokine-mediated disease (9) . In contrast, the results reported here show that the type 1 IFNs infection. Shown is a schematic representation of the differences in the immune response to LCMV in the peritoneal cavity compared to the spleen. The results presented here studying the peritoneal cavity show that both type 1 IFNs and the viral burden peak at 30 h. This is correlated with an early peak in IFN-␥ production in NK cells. NK cell production of IFN-␥ occurs before STAT1 levels have risen. Previous work with the spleen has shown that a more vigorous peak in viral load and type 1 IFNs is seen between 2 and 3 days after LCMV infection with a concurrent rise in STAT1 (7). Type 1 IFNs are unable to access STAT4-dependent IFN-␥ production due to the earlier rise in STAT1 levels. The response in the peritoneum promotes antiviral defense. The response in the spleen protects from dysregulated cytokine production and cytokine-mediated disease.