Biology Reference
In-Depth Information
Activation of Ly49H by m157
C57BL/6 mice are relatively resistant to MCMV, whereas Balb/c mice are more
susceptible due to the cmv-1 genetic locus (Scalzo et al. 1990) encoding the
Ly49 NK-cell receptor complex (Scalzo et al. 1995). Further mapping revealed
that the cmv-1 resistance trait corresponded to the Ly49H NK cell receptor
gene (Brown et al. 2001; Lee et al. 2001; Scalzo 2002; Dimasi and Biassoni
2005) and depletion of NK cells expressing Ly49H-enhanced MCMV titers in
the resistant C57BL/6 mouse strain (Daniels et al. 2001). Of note, the clearance
of MCMV by Ly49H NK cells cannot be overcome by the effects of m152
(Krmpotic et al. 2002). Since Ly49H is an activating receptor, it seemed plausi-
ble that the ligand was expressed on MCMV-infected cells. It turned out that
Ly49H directly recognizes a viral protein (Arase et al. 2002; Smith et al. 2002),
the ORF m157 encoding a predicted GPI-linked protein with structural homol-
ogy to nonclassical MHC molecules. m157 is a ligand for both the activating
receptor Ly49H and inhibitory receptor Ly49I (Arase et al. 2002; Smith et al.
2002). Thus, the effects of m157 expression depend on Ly49 receptor expres-
sion, which varies in mouse strains. Ly49 homodimerization also seems to be
crucial for the interaction with m157, which is not the case for the interaction
with MHC class I (Kielczewska et al. 2007). Deletion of the m157 gene from the
MCMV genome results in a virus that is less susceptible to the host immune sys-
tem compared to WT in Ly49H
+
mice (Bubic et al. 2004). m157 is highly varia-
ble in wild mice and several of these isolates are unable to bind to Ly49H (Voigt
et al. 2003).
Using 3D homology searches, Smith et al. predict that as many as 12 open
reading frames in the genome of MCMV show limited homology to nonclassical
MHC molecules (Arase et al. 2002; Smith et al. 2002). Moreover, MCMV mutants
lacking genes of the m02 gene family encoding additional putative type I mem-
brane glycoproteins were attenuated but grew normally upon NK cell depletion
(Oliveira et al. 2002). Thus, it seems that ligands for activating and inhibitory NK
cell receptors might be a widespread feature of the MCMV genome and that many
of the unknown open reading frames encoding glycoproteins might encode
immune-regulatory proteins. In fact, stocks of wild-derived inbred mice are natu-
rally resistant to MCMV due to NK cells, and multiple loci are responsible for this
resistance. One NK cell-dependent viral resistance mechanism was mapped to
Cmv4, which most likely encodes for a new NK activating receptor (Adam et al.
2006). Non-Ly49-depedendent MCMV resistance was also reported for NZ mice
(Rodriguez et al. 2004). In addition, MCMV resistance of MA/My mice was
mapped to H2k-linked nonclassical MHC-I genes (Dighe et al.; Xie et al. 2007).
Thus, CMVs might encode multiple, polymorphic NK cell evasion molecules to
counteract the natural resistance mediated by a host of activation receptor
combinations.
