MHC class I Dk expression in hematopoietic and nonhematopoietic cells confers natural killer cell resistance to murine cytomegalovirus

NK cell-mediated murine cytomegalovirus (MCMV) resistance (Cmv(r)) is under H-2(k) control in MA/My mice, but the underlying gene(s) is unclear. Prior genetic analysis mapped Cmv(r) to the MHC class I (MHC-I) D-k gene interval. Because NK cell receptors are licensed by and responsive to MHC class I molecules, D-k itself is a candidate gene. A 10-kb genomic D-k fragment was subcloned and microinjected into MCMV-susceptible (Cmv(s)) (MA/My.L-H2(b) x C57L)F-1 or (B6 x DBA/2)F-2 embryos. Transgenic founders, which are competent for D-k expression and germline transgene transmission, were identified and further backcrossed toMA/My. L-H2(b) or C57L mice. Remarkably, D-k expression delivered NK-mediated resistance in either genetic background. Further, NK cells with cognate inhibitory Ly49G receptors for self-MHC-I D-k were licensed and critical in protection against MCMV infection. In radiation bone marrow chimeras, NK resistance was significantly diminished when MHC-I D-k expression was restricted to only hematopoietic or nonhematopoietic cells. Thus, MHC-I D-k is the H-2(k)-linked Cmv(r) locus; these findings suggest a role for NK cell interaction with Dk-bearing hematopoietic and nonhematopoietic cells to shape NK-mediated virus immunity.