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Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912
Some, but not all, viral infections induce endogenous IL-12 to
drive NK cell IFN-
production and downstream antiviral defenses
during innate immune responses. Even though lymphocytic
choriomeningitis virus (LCMV) can be sensitive to IFN--mediated
antiviral effects, infections with this agent do not elicit IL-12 or
early IFN- in immunocompetent hosts. Studies presented here
demonstrate that LCMV infections of mice not only fail to induce IL-12,
but also modify responsiveness to exogenous IL-12 for IFN-
production. IFN- responses induced by IL-12 administration were
greatly diminished in splenic populations, but significantly increased
in serum and hepatic leukocytes, during the early course of LCMV
infections. The IFN- production was NK cell dependent, and the
compartmental dichotomy between spleen and liver was also demonstrated
in response to in vitro IL-12 stimulation. Although infections did
increase proportions and numbers of liver NK cells, changes in
responsiveness for IFN- expression could not be explained by cell
redistribution. Corroborating changes in proportions of NK cells
induced to express intracellular IFN- protein within the
compartments were observed. The reduction in ability of splenic
populations to produce IL-12-induced IFN- after infection by LCMV
was associated with decreased efficacy of administered IL-12 for
promoting IFN--dependent antiviral effects in the spleen.
Concomitantly, the maintenance of hepatic population IFN- production
was associated with preserved efficacy of administered IL-12 to elicit
IFN--dependent antiviral effects in the liver. Taken together, these
results demonstrate modifications of compartmental responses to IL-12
by viral infections and the consequences of these changes for efficacy
of cytokine therapy.
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