Compartmental differences in NK cell responsiveness to IL-12 during lymphocytic choriomeningitis virus infection.
Some, but not all, viral infections induce endogenous IL-12 to drive NK cell IFN-gamma production and downstream antiviral defenses during innate immune responses. Even though lymphocytic choriomeningitis virus (LCMV) can be sensitive to IFN-gamma-mediated antiviral effects, infections with this agent do not elicit IL-12 or early IFN-gamma 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-gamma production. IFN-gamma 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-gamma 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-gamma expression could not be explained by cell redistribution. Corroborating changes in proportions of NK cells induced to express intracellular IFN-gamma protein within the compartments were observed. The reduction in ability of splenic populations to produce IL-12-induced IFN-gamma after infection by LCMV was associated with decreased efficacy of administered IL-12 for promoting IFN-gamma-dependent antiviral effects in the spleen. Concomitantly, the maintenance of hepatic population IFN-gamma production was associated with preserved efficacy of administered IL-12 to elicit IFN-gamma-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.
Pien
G C
GC
Department of Molecular Microbiology, Division of Biology, Brown University, Providence, RI 02912, USA.
Biron
C A
CA
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002478:Cells, Cultured; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood; D018664:Interleukin-12 / Q000008:administration & dosage / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D007700:Kinetics; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000821:virology; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000821:virology
D000998:Antiviral Agents; D018664:Interleukin-12; D007371:Interferon-gamma