Biology Reference
In-Depth Information
MHC Class I Homologs and NK Cell Evasion Proteins
One strategy used by CMVs to prevent missing self is to express decoy MHC-I like
molecules that trigger inhibitory NK cell receptors.
The MHC-I homology of UL18 was originally discovered during the sequencing
of the AD169 genome (Beck and Barrell 1988). UL18 was later shown to bind
β2-microglobulin (Browne et al. 1990) and endogenous peptides (Fahnestock
et al. 1995). This ORF is conserved in chimpanzee CMV (ChCMV) (Davison
et al. 2003), but not in rhesus CMV (RhCMV) (Hansen et al. 2003). UL18 is a
ligand for the leukocyte immunoglobulin-like receptor 1 (LIR-1) (Cosman et al.
1997), an inhibitory receptor that is widely expressed in macrophages, dendritic
cells, as well as subsets of NK cells (Colonna 1998), and is the only LIR family
member expressed by T cells (Borges and Cosman 2000). LIR-1 is highly
expressed on HCMV-specific cytotoxic T lymphocytes (Antrobus et al. 2005;
Northfield et al. 2005) and on lymphocytes in lung-transplanted patients weeks
before development of CMV disease (Berg et al. 2003). The widespread expres-
sion of LIR-1 suggests multiple possible functions of UL18, but also compli-
cates the interpretation of results obtained with UL18-deleted viruses or
UL18-transfected cells. LIR-1 interacts with the α3 domain of MHC-I (Willcox
et al. 2003) but binds to UL18 1,000-fold stronger than to MHC-I (Borges et al.
1997; Cosman et al. 1997; Chapman et al. 1999). However, the UL18 gene
shows substantial strain variations that differ in their affinity to LIR-1 (Vales-
Gomez et al. 2005). UL18 is expressed on the surface of HCMV-infected cells
(Park et al. 2002; Griffin et al. 2005) and escapes the MHC-retaining or -degrading
functions of the US6 family (Park et al. 2002). However, initial results that
UL18 expression inhibited NK cell lysis through the lectin-like receptor CD94
(Reyburn et al. 1997) were later disputed since UL18 actually increased the
susceptibility of infected or transfected fibroblasts to NK cell killing (Leong
et al. 1998; Odeberg et al. 2002). Moreover, the response of CD94/NKG2C
+
NK
cells was independent of UL16, UL18, and UL40, as well as 19 clinical strain-
specific viral genes, but was impaired when cells were infected with a mutant
lacking the US2-11 gene region (Guma et al. 2006). However, fibroblasts
infected with an HCMV UL18 deletion mutant exhibited enhanced susceptibil-
ity to NKL killing (Robertson et al. 1996) relative to cells infected with the
parental virus (Prod'homme et al. 2007). While this study supports a role of
UL18 in NK evasion, others reported a T cell stimulatory function of UL18.
Co-incubation of PMBC from CMV-seropositive donors with virus-infected
lung fibroblasts leads to T cell-dependent secretion of IFN-γ, which was signifi-
cantly reduced when the lung fibroblasts were infected with a UL18 deletion
mutant (Wagner et al. 2007). Moreover, resting and activated CD8
+
T cells lysed
UL18-expressing cells irrespective of their Ag-specificity, in a non-MHC-
restricted fashion, whereas cells infected with CMV defective for UL18 were
not killed (Saverino et al. 2004). Thus, the role of UL18 in viral immune evasion
is still unclear.
