Murine Cytomegalovirus Is Regulated by a Discrete Subset of Natural Killer Cells Reactive with Monoclonal Antibody to Ly49h

Daniels, Keith A.; Devora, Gene; Lai, Wayne C.; O'Donnell, Carey L.; Bennett, Michael; Welsh, Raymond M.

Control of MCMV by an NK Cell Subset NKR region of mouse chromosome 6 somewhere between Ly49D and Prp-1 (49) . It is therefore possible that the putative Cmv-1 protein is an Ly49 molecule. This locus controls the replication of MCMV mostly in the spleen but less so in the liver (7) . NK cells mediate control of MCMV by different mechanisms in these two organs. Replication in the liver is controlled by IFN-␥, whereas replication in the spleen is controlled primarily by a perforin-dependent mechanism, suggesting cytotoxicity (18, 19) . Our assays in this study focused only on IFN-␥ production, but we presume that those 1F8 ϩ NK cells also have cytolytic activity. Indeed, our preliminary data with IFN-␥-deficient mice show that mAb 1F8 dramatically elevates spleen viral titers, consistent with an additional mechanism such as perforin being involved in control of MCMV. Depletion of the 1F8 ϩ subset in normal C57BL/6 mice affected viral titers and enhanced pathology in both spleen and liver, an observation that may be inconsistent with the effects of Cmv-1, which are noted mostly in the spleen. However, the effects on viral titers were much greater in the spleen than in the liver, possibly consistent with the Cmv-1 phenotype. It is ironic that the effects of mAb 1F8 are so profound in the spleen when, if anything, the 1F8 ϩ NK cells appear to be recruited away from the spleen and into other sites of infection. It of course is not clear whether the reductions in viral titers within the spleen are due to NK cells acting within the spleen or to NK cells controlling virus before it can get into the spleen. The relationship between Cmv-1 and the studies presented here is unclear. The Ly49H gene lies slightly outside the area in chromosome six mapped for the Cmv-1 locus (49, 50) . Thus, it may represent another factor of resistance. However, it remains possible given the complexities of the Ly49 family of related genes that the mapping is not completely accurate or that the 1F8 mAb cross-reacts with another as yet undefined Ly49 molecule mapping within the region where Cmv-1 may lie. Of note is that the influence of Cmv-1 is not strongly dependent on an MHC allotype, as this C57BL/6 (H2 b ) mouse locus has been bred into a normally sensitive Balb/c (H2 d ) background and still manifests antiviral activity (51) . Balb/c mice do not normally express Ly49H, so it would be interesting to selectively introduce this gene into the Balb/c background and determine whether it promotes resistance to MCMV.