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

NK cell-mediatedmurine cytomegalovirus (MCMV) resistance (Cmv^r) is under H-2^k control in MA/My mice, but the underlying gene(s) is unclear. Prior genetic analysismapped Cmvr to theMHC class I (MHC-I) D ^k gene interval. Because NK cell receptors are licensed by and responsive to MHC class Imolecules, 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)F₁ or (B6 x DBA/2)F₂ embryos. Transgenic founders, which are competent for D^k expression and germline transgene transmission, were identified and further backcrossed to MA/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 D^k-bearing hematopoietic and nonhematopoietic cells to shape NK-mediated virus immunity.