Impaired NK-cell education diminishes resistance to murine CMV infection

Ly49G2 (G2⁺) NK cells mediate murine (M)CMV resistance in MHC D^k-expressing mice. Bone marrow transplantation (BMT) studies revealed that G2⁺ NK cell-mediated MCMV resistance requires D^k in both hematopoietic and nonhematopoietic cells. As a Ly49G2 ligand, D^k in both cell lineages may contribute to lysis of virus-infected cells. Alternatively, cellular differences in self-MHC D^k may have affected NK-cell education, and consequently NK cell-mediated viral clearance. We investigated the D^k-licensing effect on BM-derived NK cells in BMT recipients by analyzing cytokines, cytotoxicity and MCMV resistance. In BMT recipients with lineage-restricted D^k, G2⁺ NK-cell reactivity and cytotoxicity was diminished in comparison to BMT recipients with self-MHC in all cells. Reduced G2⁺ NK-mediated MCMV resistance in BMT recipients with lineage-restricted self-MHC indicates that licensing of G2⁺ NK cells is related to NK-cell reactivity and viral control. Titrating donor BM with self-MHC-bearing hematopoietic cells, as well as adoptive transfer of mature G2⁺ NK cells into BMT recipients with self-MHC in non-hematopoietic cells only, enhanced NK-cell licensing and rescued MCMV resistance. This disparate self-MHC NK-cell education model would suggest that inadequately licensed NK cells corresponded to inefficient viral sensing and clearance.