Assessment of Cmv1 candidates by genetic mapping and in vivo antibody depletion of NK cell subsets.

The mouse chromosome 6 locus Cmv1 controls resistance to infection with murine cytomegalovirus (MCMV). We have previously shown that Cmv1 is tightly linked to members of the NK gene complex (NKC) including the Ly49 gene family. To assess the candidacy of individual NKC members for the resistance locus, first we followed the co-segregation of Cd94, Nkg2d, and the well-characterized Ly49a, Ly49c and Ly49g genes with respect to Cmv1 in pre-existing panels of intraspecific backcross mice. Gene order and intergene distances (in cM) were: centromere-Cd94/Nkg2d-(0.05)-Ly49a/Ly49c/Ly49 g/Cmv1-(0. 3)-Prp/Kap/D6Mit13/111/219. This result excludes Cd94 and Nkg2d as candidates whereas it localizes the Ly49 genes within the minimal genetic interval for Cmv1. Second, we monitored the cell surface expression of individual Ly49 receptors in MCMV-infected mice over 2 weeks. The proportion of Ly49C(+) and Ly49C/I(+) cells decreased, the proportion of Ly49A(+) and Ly49G2(+) remained constant, and the cell surface density of Ly49G2 increased during infection, suggesting that NK cell subsets might have different roles in the regulation of MCMV infection. Third, we performed in vivo antibody depletion of specific NK cell subsets. Depletion with single antibodies did not affect the resistant phenotype suggesting that Ly49A(+), Ly49C(+), Ly49G2(+) and Ly49C/I(+) populations are not substantial players in MCMV resistance, and arguing for exclusion of the respective genes as candidates for Cmv1. In contrast, mice depleted with combined antibodies showed an intermediate phenotype. Whether residual NK cells, post-depletion, belong to a particular subset expressing another Ly49 receptor, or a molecule encoded by a yet to be identified gene of the NKC, is discussed.