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Downregulation of the NKG2D Ligand MICA by UL142
The HCMV MHC-class-I-like molecule UL142, which has a homolog in ChCMV
but not in RhCMV (Davison et al. 2003; Wills et al. 2005), inhibits NK cell lysis
by downregulating MIC-A (Wills et al. 2005; Chalupny et al. 2006). Interestingly,
only the full-length alleles of MIC-A are targeted by the viral protein, whereas the
MICA 008 allele, which has a truncated transmembrane region, is not affected by
UL142 (Zou et al. 2005; Chalupny et al. 2006). MIC-A is the ligand of the activat-
ing NK cell receptor NKG2D, a lectin-like receptor that is not only expressed on
NK cells, but also on CD8 + T cells as well as γδ + T cells (Bauer et al. 1999). Since
NKG2D exists only as an activating receptor, the missing self principle does not
apply given that stimulation of NK cells is observed even if a full set of MHC I
molecules is expressed on the target cells (Bauer et al. 1999). Thus, downregula-
tion of MIC-A increases the activation threshold of NKG2D-expressing NK cells
and T cells.
Downregulation of Murine NKG2D Ligands by m138, m145,
m152, and m155
MIC proteins are not conserved in rodents. The NKG2D ligands identified in
mice include retinoic acid early inducible gene-1 (RAE-1) (Cerwenka et al.
2000), which has five different isoforms (RAE-1α, β, γ, δ, and ε), the minor
histocompatibility antigen H60 (Malarkannan et al. 1998; Diefenbach and Raulet
2003) and the murine UL16-binding protein-like transcript (MULT)-1 glycoprotein
(Carayannopoulos et al. 2002; Diefenbach et al. 2003). All three of these ligands are
targeted by MCMV to prevent NK cell activation through NKG2D. Three of the
four MCMV genes identified thus far that act on NKG2D ligands are members of
the m145 gene family (m145, m152, and m155). An initial report of the classical
MHC-evasion gene m152 playing a role in NK cell evasion in vivo (Krmpotic et al.
2002) led to the discovery that m152 reduced surface expression of all five isoforms
of RAE-1, but not H60 (Lodoen et al. 2003). H60 was later shown to be targeted for
downregulation by the m155 gene (Lodoen et al. 2004; Hasan et al. 2005) and by
the Fc receptor m138 (Lenac et al. 2006). Lastly, MULT-1 is also targeted by m138
(Lenac et al. 2006) as well as m145 (Krmpotic et al. 2005). Importantly, each study
showed that viruses that independently lack m138, m145, m152, or m155 have an
NK cell-dependent attenuation in vivo compared to wild type and revertant viruses.
The fact that MCMV targets each of the NKG2D ligands and that viruses lacking
any one of these modulators is attenuated in vivo underlines the critical importance
of this innate response to viral infection. Interestingly, m145 and m155 display
significant sequence variations among different MCMV strains, while the protein
m152 is highly conserved, which could reflect polymorphism of their respective
targets (Smith et al. 2006).
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