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.

Of all systems studied, MCMV remains, at least in our hands, the virus whose control is most dependent on NK cells. It is noteworthy that three other viruses, LCMV, MHV, and VV, that are less sensitive to control by NK cells also induced substantial infiltrates of 1F8 ϩ NK cells, many of which could be shown to spontaneously produce IFN-␥ on direct isolation ex vivo. High levels of IFN-␥ production by NK cells in MCMV-infected mice have been linked to the ability of MCMV to induce high levels of IL-12 early in infection (18, 35) . However, why 1F8 ϩ NK cells are so good at producing IFN-␥ after viral infections does not seem to be associated with any selective sensitivity to IL-12, as they are the major IFN-␥-producing cells even in mice lacking IL-12 p40 receptor (unpublished observations). The total number of NK cells and the percent of NK cells producing IFN-␥ is lower in IL-12R KO mice, but the 1F8 ϩ cells remain the predominant IFN-␥-producing cell population, accounting for Ͼ75% of the IFN-␥-producing cells. It is possible that the positively signaling Ly49H responds to a common property of virus-infected cells or, alternatively, may be primed by positively stimulating ligands in the environment even before virus infection takes place. Why are these NK cells so important for control of MCMV, but less so for the other viruses? This might relate to the fact that MCMV seemed to provide a much greater IFN-␥-producing stimulus than the other viruses under the conditions tested, but there is little question that highly active IFN-␥-producing 1F8 ϩ NK cell populations were at the sites of infection of all of those viruses. Either the other viruses are relatively resistant to the antiviral effects of NK cells, or else, in the absence of NK cells, the control of those infections is efficiently compensated for by another effector system providing innate immunity. We now know that VV can be effectively controlled by an early ␥␦ T cell response and by memory ␣␤ T cells cross-reactive with other antigens (24, 31) . Redundancy in antiviral functions would clearly be to the advantage of the host. The mechanism of the unique susceptibility of MCMV and perhaps some other herpes viruses to control by NK cells is still in need of resolution.