Cutting edge: selective IL-18 requirements for induction of compartmental IFN-gamma responses during viral infection

Optimal protective effects for defense against infection require orchestration of immune responses spanning multiple host compartments and divergent local regulation at particular sites. During murine cytomegalovirus infections known to target spleen and liver, IL-12-induced IFN-gamma from NK cells is crucial for resistance. However, the roles for IL-18 and/or IL-12 in regulating hepatic IFN-gamma responses, as compared with systemic or splenic responses, have not been defined. In this report, mice genetically deficient in either IL-18 or IL-12p35 exhibited up to 95% reductions in systemic and splenic IFN-gamma responses. Surprisingly, IFN-gamma responses were preserved in the livers of IL-18-deficient, but not IL-12p35-deficient, mice. Cytokine requirements for host survival also differed. Under conditions where mice lacking IL-12p35 exhibited 100% mortality, those lacking IL-18 survived. Taken together, our results delineate contrasting compartmental requirements for IL-18 and suggest that preservation of local, hepatic IFN-gamma production is critical for host defense during murine cytomegalovirus challenge.