Nk cell receptor/H2-Dk-dependent host resistance to viral infection is quantitatively modulated by H2q inhibitory signals

The cytomegalovirus resistance locus cmv3 has been linked to an epistatic interaction between two loci: a natural killer (nk) cell receptor gene and the major histocompatibility complex class i (mhc-i) locus. to demonstrate the interaction between cmv3 and h2k,we generated double congenic mice between ma/my and balb.k mice and an f2 cross between fvb/n (h-2q) and balb.k (h2k) mice,two strains susceptible to mouse cytomegalovirus (mcmv). only mice expressing h2k in conjunction with cmv3ma/my or cmv3fvb were resistant to mcmv infection. subsequently,an f3 cross was carried out between transgenic fvb/h2-dk and mhc-i deficient mice in which only the progeny expressing cmv3fvb and a single h2-dk class-i molecule completely controlled mcmv viral loads. this phenotype was shown to be nk cell-dependent and associated with subsequent nk cell proliferation. finally,we demonstrated that a number of h2q alleles influence the expression level of h2q molecules,but not intrinsic functional properties of nk cells; viral loads,however,were quantitatively proportional to the number of h2q alleles. our results support a model in which h-2q molecules convey ly49-dependent inhibitory signals that interfere with the action of h2-dk on nk cell activation against mcmv infection. thus,the integration of activating and inhibitory signals emanating from various mhc-i/nk cell receptor interactions regulates nk cell-mediated control of viral load. © 2011 fodil-cornu et al.