Biology Reference
In-Depth Information
MCMV m147.5 and m138
MCMV was recently shown to downregulate two co-stimulatory molecules in T
cell activation. B7.1 (CD80) is targeted to lysosomes by the Fc receptor m138
(Mintern et al. 2006) and B7.2 (CD86) cell surface expression is reduced by
m147.5 (Loewendorf et al. 2004). m147.5 encodes a predicted 23-kDa type IIIb
transmembrane protein named modB7.2, which is encoded in two exons in ORF
m147 and complementary to ORF m149. m147.5 is highly conserved among
different MCMV strains (Smith et al. 2006), which correlates with B7.2 conserva-
tion. m138 encodes a type 1 glycoprotein Fc receptor measured at 75-80 kDa
(Mintern et al. 2006). Also implicated in modulating NKG2D ligand expression
(see above in this section), m138 is able to redirect B7.1 to lysosomes independent
of its cytoplasmic tail and transmembrane domain (Mintern et al. 2006). It is
interesting to note that although deletion of the Fc receptor attenuates MCMV
in vivo, this is not due to antibody control (Crnkovic-Mertens et al. 1998).
Rather, these studies suggest that it may be due to a combination of other evasion
strategies by m138. Downregulation of the B7 costimulatory family has so
far not been reported for primate CMVs that do not contain m147.5 or m138
homologs, although HCMV does contain two distinct Fcγ receptors (Atalay et al.
2002).
Escaping the Natural Killer Cell Response
While the epitope-specific adaptive T cell response is central to the long-term
immune control of HCMV, natural killer cells (NK cells) are important during
primary infection prior to the onset of the adaptive immune response (reviewed
by Tay et al. 1998). There is also some evidence that humans with defects in their
NK cell response are extremely susceptible to infections by herpesviruses (Biron
et al. 1989). NK cells are regulated by the integration of activatory and inhibitory
signals generated by a set of cell surface receptors that is unique to each NK cell
clone (reviewed by Lanier 1998). In primates, the killer cell immunoglobulin-like
receptor (KIR) family binds to HLA-A,B,C, and G. KIRs are composed of acti-
vating and inhibitory molecules and the clonotypic array of receptors determines
the specificity of each NK cell clone with regard to their MHC-I recognition.
Mice do not have KIR receptors. Instead, KIR-analogous functions are performed
by the Ly49 family of lectin-like receptors. A general rule is that NK cells cannot
kill cells expressing a full complement of autologous MHC-I allotypes, but can
kill cells lacking MHC-I (missing self). As a result of MHC-I downregulation,
CMV-infected cells should be excellent targets for NK cells. Indeed, increased
lysis of HCMV-infected cells, as well as cells transfected with viral MHC-
evasion genes, can be observed for some human NK cell clones (Huard and Fruh
2000). However, HCMV has also devised clever strategies to prevent NK cell
activation.
