MHC class I Dk gene expression licenses Ly49G2+ NK cell function and rescues MCMV susceptibility (128.19)

Abstract

Abstract NK cell-mediated murine CMV (MCMV) resistance is under H-2k genetic control in MA/My mice, however the underlying gene(s) is unclear. We generated a panel of intra-H-2 recombinant congenic mouse strains to map a 0.3-Mb critical interval in the H-2 class I D subregion. The interval spans 30 genes including the class I Dk gene. Because Ly49 NK cell receptors are licensed by and responsive to MHC class I molecules, Dk is a positional candidate. Thus, a 10-kb Dk genomic DNA was cloned and injected into MCMV susceptible (Cmvs) (MA/My.L-H2b x C57L)F1 blastocysts. A transgenic founder (Tg3-Dk) mouse was healthy and competent in germline transgene transmission. We separately backcrossed Tg3-Dk to both C57L and MA/My.L-H2b Cmvs genetic backgrounds and found that Dk was expressed at the cell surface of leukocytes only in Tg3-Dk offspring. Importantly, Tg3-Dk gene expression conferred virus resistance; Tg3-Dk offspring spleens had ~1000-fold lower MCMV at 90 h after infection than non-transgenic littermate controls. MCMV resistance in this system may need Dk-licensed Ly49G2+ NK cells. In support, we have found that Ly49G2+ NK cells are selectively licensed in, and preferentially expand and become activated during MCMV infection in Dk-expressing C57L.M-H2k(R7) congenic mice. This is under study in Tg3-Dk mice. We conclude that Dk gene expression is essential in H-2k MCMV resistance. Supported by NIH R01 AI50072.