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Transgenic Expression of the Activating Natural Killer Receptor Ly49H Confers Resistance to Cytomegalovirus in Genetically Susceptible Mice

Seung-Hwan Lee¹, Ahmed Zafer², Yves de Repentigny², Rashmi Kothary², Michel L. Tremblay³, Philippe Gros³, Pascale Duplay⁴, John R. Webb¹ and Silvia M. Vidal¹

¹ Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada
² Centre for Molecular Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada
³ Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada
⁴ Institut National de la Recherche Scientifique-Institut Armand-Frappier, Universite du Quebec, Laval, Quebec H7V 1B7, Canada

Address correspondence to Silvia M. Vidal, Faculty of Medicine, University of Ottawa, Room 4207, 451 Smyth Rd., Ottawa, Ontario K1H 8M5, Canada. Phone: 613-562-5800 (8592); Fax: 613-562-5452; E-mail: svidal{at}uottawa.ca

Natural resistance to infection with mouse cytomegalovirus (MCMV) is controlled by a dominant locus, Cmv1. Cmv1 is linked to the Ly49 family of natural killer receptors on distal chromosome 6. While some studies localized Cmv1 as distal to the Ly49 gene cluster, genetic and functional analysis identified Ly49h as a pivotal factor in resistance to MCMV. The role of these two independent genomic domains in MCMV resistance was evaluated by functional complementation using transgenesis of bacterial artificial chromosomes (BAC) in genetically susceptible mice. Phenotypic and genetic characterization of the transgenic animals traced the resistance gene to a single region spanning the Ly49h gene. The appearance of the Ly49H protein in NK cells of transgenic mice coincided with the emergence of MCMV resistance, and there was a threshold Ly49H protein level associated with full recovery. Finally, transgenic expression of Ly49H in the context of either of the two independent susceptibility alleles, Cmv1^sBALB or Cmv1^sFVB, conferred resistance to MCMV infection. These results demonstrate that Ly49h is necessary and sufficient to confer MCMV resistance, and formally demonstrate allelism between Cmv1 and Ly49h. This panel of transgenic animals provides a unique resource to study possible pleiotropic effect of Cmv1.

Key Words: genetic complementation test • natural immunity • animal model • immunogenetics • natural killer cells

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