NATURAL KILLER CELL RECOGNITION OF VIRAL INFECTION: PAIRED MHC I RECEPTORS FACILITATE VIRAL DETECTION AND CLEARANCE

NK cells play a critical role in controlling MCMV infection. We have shown that MHC class I Dk is absolutely required for murine host protection to MCMV infection and MHC class I Dk-dependent MCMV resistance is reliant upon NK cells marked by the MHC class I Dk inhibitory receptor, Ly49G2. Ly49G2 binds MHC class I Dk and educates NK cells on self-MHC class I which causes them to exhibit enhance sensitivity to activation receptor stimulation. Despite this, a role for specific activation receptors in MHC class I Dk-dependent MCMV resistance has not been delineated. We identified the Ly49R activation receptor as a novel mediator of MHC class I Dk-dependent MCMV resistance by selective neutralization via a specific monoclonal antibody. We also precisely define the role of Ly49G2 in MHC class I Dk-dependent MCMV resistance via specific genetic ablation of Ly49G2. Additionally, we discovered that NK cells require simultaneous expression of Ly49G2 and Ly49R to selectively control MCMV infection, proliferate, differentiate to terminal effector cells, and exhibit other features of specific activation. This original work demonstrates that paired MHC I receptors work in tandem to confer viral immunity.