title: The effect of the Cmv-1 resistance gene, which is linked to the natural killer cell gene complex, is mediated by natural killer cells.
abstract: The resistance of mice to lethal infection by murine CMV (MCMV) is under complex host genetic control with contributions from both H-2 and non-H-2 genes. We have previously shown that an autosomal, non-MHC encoded gene, Cmv-1, controls MCMV replication in the spleen. We have investigated the mechanism by which the Cmv-1 resistance gene confers protection against MCMV infection. Using H-2 compatible irradiation bone marrow chimeras, the enhanced resistance to MCMV infection that is associated with the Cmv-1l allele in the C57BL background was shown to be mediated by an irradiation-sensitive bone marrow-derived cell population, or a factor produced by these cells. The lack of correlation between serum IFN titers and the strain distribution pattern of Cmv-1 in CXB recombinant inbred mouse strains suggests that IFN does not mediate resistance conferred by this gene. Similarly, the lack of effect of in vivo depletion of mature CD4+ and CD8+ T cells on virus replication in C57BL/6J mice indicates that T cells are unlikely to be involved. In contrast, in vivo depletion of NK cells by injection of the anti-NK1.1 mAb PK136 abrogated restricted splenic virus replication in C57BL/6J----BALB.B chimeric mice and in the Cmv-1l CXB strains. These data indicate that the effect of the Cmv-1 gene is mediated by NK cells. The significant augmentation in NK cell activity after MCMV infection of the susceptible Cmv-1h strains (BALB/cBy), CXBG/By, CXBH/By, CXBI/By, and CXBK/By) indicates the existence in these mice of NK cells that are functionally and phenotypically distinct from those in Cmv-1l strains. NK cells present in the Cmv-1h strains are unable to restrict efficiently splenic MCMV replication in vivo, possibly due to a lack of specificity for virus-infected target cells. Finally, flow cytometric analysis of NK1-1 expression in CXB and BXD RI mice together with MCMV replication studies in the BXD RI strains indicate that Cmv-1 is closely linked to NK1.1 and other loci that reside on a distal segment of murine chromosome 6 in a region that has recently been defined as the natural killer complex.
authors.affiliation: Department of Microbiology, University of Western Australia, Queen Elizabeth II Medical Centre, Nedlands.
authors.forename: A A
authors.initials: AA
authors.lastname: Scalzo
authors.forename: N A
authors.initials: NA
authors.lastname: Fitzgerald
authors.forename: C R
authors.initials: CR
authors.lastname: Wallace
authors.forename: A E
authors.initials: AE
authors.lastname: Gibbons
authors.forename: Y C
authors.initials: YC
authors.lastname: Smart
authors.forename: R C
authors.initials: RC
authors.lastname: Burton
authors.forename: G R
authors.initials: GR
authors.lastname: Shellam
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D003586:Cytomegalovirus Infections / Q000235:genetics* / Q000276:immunology; D005260:Female; D005796:Genes; D007372:Interferons / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology / Q000502:physiology*; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000382:microbiology; D014779:Virus Replication
chemical_list: D007372:Interferons