Deficient major histocompatibility complex-linked innate murine cytomegalovirus immunity in MA/My.L-H2b mice and viral downregulation of H-2k class I proteins.
NK cells are key effectors of innate immunity and host survival during cytomegalovirus (CMV) infection. Innate murine CMV (MCMV) resistance in MA/My mice requires Ly49H/m157-independent H-2k-linked NK cell control. Here we show that replacement of MA/My H-2k with C57L H-2b susceptibility genes led to a remarkable loss of innate virus immunity, though NK gamma interferon was induced in H-2b and H-2k strains shortly after infection. Thus, H-2b genes expressed in C57L or MA/My.L-H2b are sufficient in alerting NK cells to intrusion but fail to support NK restraint of viral infection. In addition, novel H-2 recombinant strains were produced and utilized in a further refinement of a critical genetic interval controlling innate H-2k-linked MCMV resistance. Importantly, this analysis excluded the gene interval from Kk class I through class II. The responsible gene(s) therefore resides in an interval spanning Dk class Ia and more-distal major histocompatibility complex (MHC) nonclassical class Ib genes. Recently, the NK activation receptor Ly49P and MHC class I Dk proteins were genetically implicated in MCMV resistance, in part because Ly49P-expressing reporter T cells could specifically bind Dk molecules on MCMV-infected mouse embryonic fibroblasts (MEFs). However, as we found that H-2k innate resistance differs in the C57L or MA/My backgrounds and because MCMV very efficiently downregulates H-2k class I proteins in L929 cells and primary MEFs shortly after infection, a Ly49P/Dk model should not fully explain H-2k-linked MCMV resistance.
Xie
Xuefang
X
Department of Internal Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Dighe
Abhijit
A
Clark
Patricia
P
Sabastian
Pearl
P
Buss
Sarah
S
Brown
Michael G
MG
D000818:Animals; D015536:Down-Regulation; D006183:H-2 Antigens / Q000235:genetics / Q000378:metabolism*; D006566:Herpesviridae Infections / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008285:Major Histocompatibility Complex; D051379:Mice; D008815:Mice, Inbred Strains; D018146:Muromegalovirus / Q000276:immunology* / Q000472:pathogenicity / Q000502:physiology; D014779:Virus Replication
D006183:H-2 Antigens; D007371:Interferon-gamma