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MHC Class I D^k Locus and Ly49G2⁺ NK Cells Confer H-2^k Resistance to Murine Cytomegalovirus¹

Xuefang Xie^*, Michael D. Stadnisky^* and Michael G. Brown^2,*,

^* Department of Microbiology and Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908

Essential NK cell-mediated murine CMV (MCMV) resistance is under histocompatibility-2^k (H-2^k) control in MA/My mice. We generated a panel of intra-H2^k recombinant strains from congenic C57L.M-H2^k/b (MCMV resistant) mice for precise genetic mapping of the critical interval. Recombination breakpoint sites were precisely mapped and MCMV resistance/susceptibility traits were determined for each of the new lines to identify the MHC locus. Strains C57L.M-H2^k(R7) (MCMV resistant) and C57L.M-H2^k(R2) (MCMV susceptible) are especially informative; we found that allelic variation in a 0.3-megabase interval in the class I D locus confers substantial difference in MCMV control phenotypes. When NK cell subsets responding to MCMV were examined, we found that Ly49G2⁺ NK cells rapidly expand and selectively acquire an enhanced capacity for cytolytic functions only in C57L.M-H2^k(R7). We further show that depletion of Ly49G2⁺ NK cells before infection abrogated MCMV resistance in C57L.M-H2^k(R7). We conclude that the MHC class I D locus prompts expansion and activation of Ly49G2⁺ NK cells that are needed in H-2^k MCMV resistance.

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 National Institute of Allergy and Infectious Disease, National Institutes of Health Grant R01 AI050072.

² Address correspondence and reprint requests to Dr. Michael G. Brown, Center for Immunity, Inflammation, and Regenerative Medicine, Division of Nephrology, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908. E-mail address: mgb4n{at}virginia.edu

³ Abbreviations used in this paper: KIR, killer Ig-related receptor; Cmv^r, MCMV resistant; Cmv^s, MCMV susceptible; MCMV, murine CMV; NKC, NK gene complex; Mb, megabase; SGV, salivary gland virus; SNP, single nucleotide polymorphism; SSLP, simple sequence length polymorphism.

⁴ The online version of this article contains supplemental material.