Major histocompatibility complex class I-restricted protection against murine cytomegalovirus requires missing-self recognition by the natural killer cell inhibitory Ly49 receptors

Viruses have evolved strategies that highlight critical, intertwined host immune mechanisms. As postulated by the missing-self hypothesis, natural killer (NK) cells and major histocompatibility complex class I (MHC-I)-restricted cytotoxic T lymphocytes (CTLs) have opposing requirements for ubiquitously expressed MHC-I molecules. Since NK cell MHC-I-specific Ly49 inhibitory receptors prevent killing of cells with normal MHC-I, viruses evading CTLs by down-regulating MHC-I should be vulnerable to NK cells. However, definitive integrated in vivo evidence for this interplay has been lacking, in part due to receptor polymorphism and a proposed second function of Ly49 receptors in licensing NK cells via self-MHC-I. Here we generated mice lacking specific Ly49 inhibitory receptors to show their essential role in licensing and controlling murine cytomegalovirus (MCMV) infection in vivo in an MHC-restricted manner. When MCMV cannot down-regulate MHC-I, NK cells cannot control infection that instead is mediated by CTLs, as predicted by the missing-self hypothesis.