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* Department of Human Genetics and
McGill Centre for the Study of Host Resistance, McGill University, Montreal, Quebec, Canada;
Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912;
Laboratory of Molecular Immunology, Institut de Recherches Cliniques de Montréal, Université de Montréal, Montréal, Quebec, Canada; and
¶ Department of Molecular Microbiology and Immunology, Saint Louis University Medical School, St. Louis, MO 63104
Cmv1 was the first mouse cytomegalovirus (MCMV) resistance locus identified in C57BL/6 mice. It encodes Ly49H, a NK cell-activating receptor that specifically recognizes the m157 viral protein at the surface of MCMV-infected cells. To dissect the effect of the Ly49h gene in host-pathogen interactions, we generated C57BL/6 mice lacking the Ly49h region. We found that 36 h after MCMV infection, the lack of Ly49h resulted in high viral replication in the spleen and dramatically enhanced proinflammatory cytokine production in the serum and spleen. At later points in time, we observed that MCMV induced a drastic loss in CD8+ T cells in B6.Ly49h–/– mice, probably reflecting severe histological changes in the spleen. Overall, our results indicate that Ly49H+ NK cells contain a systemic production of cytokines that may contribute to the MCMV-induced pathology and play a central role in maintaining normal spleen cell microarchitecture. Finally, we tested the ability of B6.Ly49h–/– mice to control replication of Leishmania major and ectromelia virus. Resistance to these pathogens has been previously mapped within the NK gene complex. We found that the lack of Ly49H+ NK cells is not associated with an altered resistance to L. major. In contrast, absence of Ly49H+ NK cells seems to afford additional protection against ectromelia infection in C57BL/6 mice, suggesting that Ly49H may recognize ectromelia-infected cells with detrimental effects. Taken together, these results confirm the pivotal role of the Ly49H receptor during MCMV infection and open the way for further investigations in host-pathogen interactions.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Canadian Institutes of Health Research Grant MOP-7781 (to S.M.V.) and by National Institutes of Health Grant CA41268 (to C.A.B.).
2 Address correspondence and reprint requests to Dr. Silvia M. Vidal, Department of Human Genetics, McGill Duff Medical Building, 3775 University Street, Montreal, H3A 2B4 QC Canada. E-mail address: silvia.vidal{at}mcgill.ca
3 Abbreviations used in this paper: MCMV, mouse CMV; NKC, NK gene complex; ECTV, ectromelia virus; DC, dendritic cell; pDC, plasmacytoid DC; p.i., postinfection; MHC-II, MHC class II.
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