Biology Reference
In-Depth Information
Sequencing of the MCMV genome also revealed an MCMV-MHC I homolog,
m144, (Rawlinson et al. 1996), which also binds to β2-microglobulin but does
not seem to bind peptides (Chapman and Bjorkman 1998) due to a misfolded
peptide binding domain (Natarajan et al. 2006). m144 is polymorphic (Smith
et al. 2006) and partially inhibits NK cell responses in vitro (Kubota et al.
1999). A role of m144 in NK cell evasion is supported by the finding that rep-
lication of m144-deleted MCMV is restricted in vivo, but normal upon NK cell
depletion (Farrell et al. 1997). However, the receptor for m144 is currently
unknown.
The UL40 Protein
The inhibitory CD94/NKG2A receptor recognizes the nonpolymorphic human
HLA-E or mouse Qa-1b molecule (Lee et al. 1998). HLA-E displays signal
sequence peptides of classical MHC-I molecules at the cell surface, thus allow-
ing NK cells to monitor MHC-I expression in parallel to interaction of MHC-I
with the KIR/Ly49 family (Braud et al. 1997; Vance et al. 1998; Ulbrecht et al.
2000). Remarkably, the glycoprotein UL40 of HCMV encodes a signal sequence
that is identical to that of classical HLA-C molecules and can thus be presented
by HLA-E (Tomasec et al. 2000; Ulbrecht et al. 2000). Loading of the UL40
signal peptide is independent of TAP, whereas the loading of HLA-signal
sequences is TAP-dependent. Thus, HCMV ensures surface expression of high
levels of peptide-loaded HLA-E, even upon TAP inhibition by US6 and MHC-I
destruction by US2-US11. In vitro experiments showed that fibroblasts infected
with wild type, but not UL40-deleted HCMV were protected against lysis by
CD94/NKG2A-positive NK cell lines as well primary NK cells (Wang et al.
2002). Thus it was concluded that HCMV counteracts NK cell activation by the
US6 family, at least for NKG2A-expressing NK cell clones. However, this was
disputed by another study that found increased recognition of US2-11-deleted
HCMV regardless of the presence or absence of UL40 (Falk et al. 2002).
Moreover, it was recently shown that NK-CTLs (CD3
+
CD8
+
TCRαβ
+
) recognize
peptides in an HLA-E restricted fashion (Pietra et al. 2001; Romagnani
et al. 2002, 2004; Moretta et al. 2003). NK-CTLs efficiently killed CMV-infected
cells by recognizing the HLA-E presented UL40-derived peptide VMAPRTLIL
(identical to HLA-C) resulting in the induction of cytotoxicity, IFN-γ production,
and cell proliferation (Pietra et al. 2003; Mazzarino et al. 2005). Strain variants
of UL40 further encode other HLA-E-binding peptides (Tomasec et al. 2000;
Cerboni et al. 2001). The VMAPRTLIL-sequence is identical in chimpanzee and
gorilla MHC-I, but it is not known whether the slightly altered sequence
(TMAPKTLLI) of the ChCMV UL40 homolog can serve as a decoy for HLA-E.
There is currently no evidence that MCMV or RhCMV displays a similar evasion
mechanism.
