Biology Reference
In-Depth Information
NK Cell Modulation by UL14 and UL141
UL14 and UL141 show significant homology and have been grouped into the UL14
family (Davison et al. 2003). UL141 resides in the ER and retains the poliovirus
receptor (CD155) (Tomasec et al. 2005), a ligand for the activating NK receptors
DNAM-1 (CD226) and TACTILE (CD96). UL141 showed specificity for CD155
in that it did not influence the expression of nectin-2 (CD112), another reported
ligand for CD226 (Bottino et al. 2003).
UL14 also encodes an EndoH-sensitive, ER-resident glycoprotein that pro-
vides efficient protection to NK cell-mediated attack by NK cell lines and inter-
feron-activated bulk cultures in allogeneic and autologous assays. Although
exhibiting homology to UL141, the mechanism of UL14-mediated protection
seems to be different from UL141. In contrast to several other NK cell evasion
molecules, the UL14 family is highly conserved among different HCMV strains
(Ma et al. 2006) (although UL141 is often lost in laboratory isolates). Moreover,
homologous proteins are found in both human and nonhuman primate CMVs
(Davison et al. 2003; Hansen et al. 2003). This conservation suggests that
retaining the respective NK cell ligands is important for the pathogenesis of
primate CMVs.
Retention of NKG2D Ligands by UL16
During a search for ligands of the nonessential HCMV-glycoprotein UL16, MIC-B,
a nonpolymorphic, stress-induced MHC-I-like protein, but not MIC-A, was
observed to bind to UL16 (Cosman et al. 2001). In addition, two members of a
novel family of GPI-linked proteins, termed UL-binding proteins (ULBP1 and
ULBP2) were observed to bind to UL16 (Kubin et al. 2001), whereas the other two
members of that family (ULBP3 and ULBP4) did not (Rolle et al. 2003; Welte
et al. 2003). The specificity of UL16 in binding only some of these closely related
family members seems to be due to sequence differences in their α2 domain, which
could be shown for MIC-A and MIC-B (Spreu et al. 2006). ULBPs show a low
homology to MHC-I as well as to MIC. However, they lack the α3 domain and do
not bind β2m. Importantly, ULBP1 and ULBP2 bind to NKG2D and thus seem to
be able to stimulate NK cell as well as T cell activity in a manner that is similar
to MIC (Sutherland et al. 2002). This binding can be inhibited by UL16, which
counteracts the cell surface expression of the NKG2D ligands by retaining them in
the ER (Dunn et al. 2003; Rolle et al. 2003; Welte et al. 2003; Wu et al. 2003). ER
localization of UL16 requires the transmembrane and cytoplasmic domains (Vales-
Gomez and Reyburn 2006), while the ectodomain is associated with ULBP1,
ULBP2, and MICB.
