ABSTRACT
Natural killer (NK) cells play critical roles in antiviral immunity. While the importance of effector mechanisms such as interferons has been demonstrated through knockout mice, specific mechanisms of how viruses are recognized and controlled by NK cells are less well defined. Previous genetic studies have mapped the resistance genes for murine cytomegalovirus (MCMV), herpes simplex virus-1 (HSV-1), and ectromelia virus to the NK gene complex on murine chromosome 6, a region containing the polymorphic Ly49 and Nkrp1 families. Genetic resistance to MCMV in C57BL/6 has been attributed to Ly49H, an activation receptor, through susceptibility of the recombinant inbred strain BXD-8 that lacks Ly49h (also known as Klra8) but derived about half of its genome from its DBA/2 progenitor. However, it remained possible that epigenetic effects could account for the MCMV phenotype in BXD-8 mice. Herein, we report the generation of a novel congenic murine strain, B6.BXD8-Klra8 ( Cmv1-del )/Wum, on the C57BL/6 genetic background to evaluate the effect of deletion of a single NK activation receptor, Ly49H. Deletion of Ly49H rendered mice much more susceptible to MCMV infection. This increase in susceptibility did not appear to be a result of a difference in NK cell expansion or interferon-gamma (IFN-gamma) production between the C57BL/6 and the B6.BXD8 strains. On the other hand, the deletion of Ly49h did not otherwise affect NK cell maturation or Ly49D expression and had no effect on susceptibility to HSV-1 or ectromelia virus. In conclusion, Ly49h is necessary for genetic resistance to MCMV, but not HSV-1 or ectromelia virus.
Subject(s)
Cytomegalovirus Infections/virology , Muromegalovirus/pathogenicity , NK Cell Lectin-Like Receptor Subfamily A/physiology , Animals , Blotting, Southern , Cytomegalovirus Infections/genetics , Cytomegalovirus Infections/immunology , Female , Flow Cytometry , Genotype , Herpes Simplex/genetics , Herpes Simplex/immunology , Herpes Simplex/virology , Herpesvirus 1, Human/genetics , Herpesvirus 1, Human/immunology , Herpesvirus 1, Human/pathogenicity , Killer Cells, Natural , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Microsatellite Repeats , Muromegalovirus/genetics , Muromegalovirus/immunology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Survival RateABSTRACT
The natural killer (NK) gene complex (NKC) encodes orphan lectin-like NK cell receptors that may explain uncharacterized NK cell specificities. Unlike other NKC-encoded receptors that recognize molecules with major histocompatibility complex (MHC) class I folds, here we show that mouse Nkrp1d and Nkrp1f bind specific C-type lectin-related (Clr) molecules. Nkrp1d mediated inhibition when recognizing Clrb, a molecule expressed in dendritic cells and macrophages. Nkrp1 (official gene name, Klrb1) and Clr are intertwined in a genetically conserved NKC region showing recombination suppression, reminiscent of plant self-incompatibility loci. Thus, these findings broaden the 'missing-self' hypothesis from solely involving MHC class I to including related NK cell receptors for lectin-like ligands, and reflect genetic strategies for biological self-recognition processes in other species.
Subject(s)
Antigens, Surface/metabolism , Killer Cells, Natural/metabolism , Lectins, C-Type/metabolism , Animals , Antigens, Surface/genetics , Dendritic Cells/metabolism , Genetic Linkage , Lectins, C-Type/genetics , Ligands , Mice , NK Cell Lectin-Like Receptor Subfamily BABSTRACT
There has been marked progress in our understanding of the role of natural killer (NK) cells in immune responses, mainly due to the identification of NK-cell receptors and their ligands. The genes encoding many NK-cell receptors are located in the NK-gene complex (NKC). Here, we review the properties of NKC-encoded receptors, and provide a genomic and conceptual framework for an insight into NK-cell function and biology.
