NKG2D signaling enhances Natural Killer cell responses but alone is insufficient to drive expansion during mouse cytomegalovirus infection

Natural killer (NK) cells play a critical role in host defense against viruses. Here, we investigated the role of NKG2D in the expansion of NK cells after mouse cytomegalovirus (MCMV) infection. Wild-type and NKG2D-deficient (Klrk1−/−) Ly49H+ NK cells robustly proliferated when infected with MCMV strains engineered to allow expression of NKG2D ligands, which enhanced the response of wild-type NK cells. Naïve NK cells exclusively express NKG2D-L, which pairs only with DAP10, whereas NKG2D-S expressed by activated NK cells pairs with both DAP10 or DAP12, similar to Ly49H. However, NKG2D alone was unable to drive robust expansion of Ly49H− NK cells when mice were infected with these MCMV strains likely because NKG2D-S was only transiently expressed after infection. These findings demonstrate that NKG2D augments Ly49H-dependent proliferation of NK cells; however, NKG2D signaling alone is inadequate for expansion of NK cells, likely due to only transient expression of a NKG2D-DAP12 complex.