MHC control of virus immunity through NK cells

NK cells play an essential role in host defense against MCMV infection. Although the control mechanism in C57BL/6 mice has been extensively studied, mechanisms utilized by NK cells to recognize MCMV in other genetic systems are mostly unknown. Previous work has shown that NK cells mediate H-2k dependent MCMV control in MA/My mice. This dissertation was designed to identify the H-2k linked resistance locus (Cmvr) and to better understand the role of interaction between NK cells and H-2 Cmvr in MCMV control.

First, the essential role of H-2k was confirmed in the H-2 congenic MA/My.L-H2b strain. Further, a panel of intra-H2 recombinant congenic strains was produced and Cmvr was precisely mapped to a 0.3-Mb interval in the H-2 D subregion. Since NK Ly49 receptors recognize MHC class I proteins, the class I Dk gene was considered an excellent relevant positional candidate. Finally, Dk transgenic mice were generated and studied for innate MCMV immunity. We proved that Dk alone is sufficient to confer NK cell dependent MCMV resistance.

Since MCMV infection efficiently downregulates H-2k class I proteins, inhibitory Ly49 receptors that recognize MHC class I deficiency were brought to our attention. Interestingly, we found that a receptor for MHC-I Dk, Ly49G2, was responsible for NK mediated MCMV control in H-2k congenic R7 and Dk transgenic mice. In support of this finding, selective expansion and activation of the Ly49G2+ subset was only found in Dk expressing mice. Thus, NK cell recognition of MCMV infected cells may involve a Ly49G2-Dk interaction.

This dissertation identifies Dk as the H-2k Cmvr locus and determines a critical role for the inhibitory Ly49G2 receptor in virus immunity by acting through a particular class I allele, Dk. This finding has important implications for how the MHC shapes NK immunity.