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.

It had not been clear whether NK subset distinctions really mattered in the control of viral infections in vivo. Bone marrow transplants display the types of molecules (class I) known to be ligands for Ly49 molecules and other NKRs, but virus infections are entirely different entities, and viral replication could well be controlled by purely nonspecific inflammatory mechanisms that have nothing to do with NK subsets or NK cell recognition. For instance, relatively nonspecific inflammatory mediators such as type I IFN, TNF-␣, IL-2, IL-12, IL-15, and MIP-1␣ can contribute to the activation and proliferation of NK cells and their infiltration into tissues (41) . Those NK cells may be highly cytolytic and be nonspecifically producing copious amounts of IFN-␥, which could control infection without any form of recognition. In fact, it had been suggested that a reason why MCMV but not LCMV is susceptible to NK cells is that MCMV induces more IL-12, which in turn, enables NK cells to produce more IFN-␥ (35, 41) . This hypothesis is challenged by the fact that in mice dually infected with both MCMV and LCMV, only MCMV is controlled by NK cells (42) . Alternatively, NK cell subsets could matter, if the virus changes the expression level of MHC class I antigens on infected cells (43) , if it qualitatively alters the nature of a class I molecule by the insertion of a virus-encoded peptide (44, 45) , or if the virus encodes its own class I molecule (46) . MCMV indeed does downregulate host MHC expression and does encode a class I molecule, m144; experiments to date, however, have indicated that its class I homologue may make MCMV more resistant, rather than sensitive to NK cells, perhaps by interacting with a negatively signaling NKR (46) . The possibility also exists that a virus might encode a surface glycoprotein that directly triggers an NK cell subset, and a substantial amount of work done before the discovery of NKRs had indicated that many purified viral glycoproteins can trigger NK cells (47, 48) .