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.

This is the first demonstration that the antiviral properties of NK cells in vivo can be mediated by discrete NK cell subsets but not by others. Our results show that the NK cell subsets defined by mAb 1F8 substantially increase at sites of MCMV infection and account for Ͼ80% of the IFN-␥producing cells. mAb depletion of this subset in vivo resulted in substantially higher titers of MCMV (but not LCMV or VV); depletion of no other two or even four Ly49-expressing subsets gave comparable results (22) . The importance of different subsets in mediating other NK celldependent functions, in particular that of bone marrow allograft rejection, has been shown previously (21, 40) . The mechanism of NK cell subset recognition of allografts is clarifying, at least in some aspects. NK cell subsets displaying Ly49 receptors that are negatively signaled by MHC class I displayed by the graft are ineffective at mediating rejection. However, recently we have shown that NK cells lacking inhibitory receptors but expressing allo-MHC positive-signaling receptors, such as Ly49D, are most effective at eliciting graft rejection (40) . mAb 1F8 cross-reacts between the very closely related Ly49 C, I, and H, but costaining and in vivo depletion experiments with mAb 5E6, which recognizes Ly49C/I, indicated that those reactivities did not account for the efficacy of the Ab. Hence, it is noteworthy that the presence of a positively signaling ligand, Ly49H, may be necessary for anti-viral activity, just as a positive-signaling Ly49 is crucial for bone marrow rejection.