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*
Graduate School of Biotechnology, Korea University, and
Catholic Institutes of Medical Science, Catholic University of Korea, Seoul, Korea; and
Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Korea
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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2-microglobulin and peptides led to the hypothesis that
if the US and UL18 gene products coexist temporally during
infection, the US proteins might down-regulate UL18 molecules, similar
to their action on MHC class I molecules. We show here that temporal
expression of US and UL18 genes partially overlaps during infection.
However, unlike MHC class I molecules, the MHC class I homolog, UL18,
is fully resistant to the down-regulation associated with the US2, US3,
US6, and US11 gene products. The specific effect of US proteins on MHC
class I molecules, but not on UL18, represents another example of how
viral proteins have evolved to evade immune surveillance, avoiding
fratricide by specifically targeting host
proteins. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-herpesvirus, contributes to the high morbidity and mortality of
immunocompromised patients, most notably organ transplant recipients
and AIDS patients (1). HCMV exists ubiquitously in
human populations worldwide, and a primary infection is followed by
lifelong persistence of the virus in the host. A major immune defense
of host cells against HCMV, and viral infections in general, is
mediated by CTL, which recognize and lyse infected cells upon
engagement of the TCR with MHC class I molecules presenting viral
peptides (2). With the selective pressure of the host
immune response, several strategies have evolved for HCMV to
down-regulate HLA-A and -B expression on the surface of infected cells
(3). At present, four different gene products of the
unique short region protein (US), US2, US3, US6, and US11, have been
identified, each independently capable of reducing class I H chain
expression on the cell surface. The US2 and US11 gene products induce
rapid export of the class I H chains out of the endoplasmic reticulum
(ER) into the cytosol where the H chains are degraded by proteasomes
(4, 5). US3 expression causes MHC class I molecules to
accumulate in the ER by preventing the transport of the assembled class
I Ags to the cell surface (6, 7). Furthermore, US6
prevents peptide loading of the MHC class I molecules by inhibiting
TAP-mediated peptide translocation into the ER. The US6 gene product
encodes a type I transmembrane glycoprotein that binds directly to TAP
in the ER lumen, consequently inhibiting peptide translocation
(8, 9, 10).
Although interference with class I-mediated Ag presentation or class I
expression might enable infected cells to evade virus-specific T cells,
it might also render these cells susceptible to detection and lysis by
NK cells, which express both activating and inhibitory surface
receptors. The activating receptors are predominantly triggered by
non-MHC molecules, whereas the inhibitory receptors recognize MHC class
I molecules (11). Stimulation of activating receptors
leads to target cell lysis unless the NK cell inhibitory receptors are
able to engage an adequate level of self class I molecules on the
target cell (12). Therefore, infected cells with class I
molecules that have been down-regulated to a level sufficient to avoid
T cells can be recognized and eliminated by NK cells. However, unique
long region protein 18 (UL18), an HCMV-encoded MHC class I homolog,
might provide a mechanism for undermining the host NK cell response
(13). The HCMV-encoded homolog, UL18, is a 348-aa residue
type I transmembrane glycoprotein whose extracellular region shares
25% amino acid sequence homology with the extracellular regions of
human MHC class I molecules (13). Like MHC class I
molecules, UL18 associates with
2-microglobulin (2m)
(14), and UL18 expressed in Chinese hamster ovary cells
binds a mixture of endogenous peptides that are similar to peptides
eluted from class I molecules (15). The sequence
similarities between MHC class I molecules and UL18 along with the
ability of UL18 to form trimeric complexes with
2m and peptides suggest that the US proteins
might act on UL18 in a manner analogous to their action on MHC class I
molecules. In supporting of this hypothesis, UL18 glycoprotein has not
been detected on the surface of HCMV-infected cells, while it is
readily detected on cells transfected with the UL18 gene (14, 16). The down-regulation of UL18 expression on the cell surface
by US proteins might expose the cells to NK-mediated lysis. Two
mechanisms can be envisaged by which HCMV could counteract this threat:
the virus might temporally express US proteins and UL18 at different
times during infection, or UL18 might be intrinsically insensitive to
the action of US proteins.
We report that, unlike MHC class I molecules, the cell surface expression of UL18 was not influenced by any of the HCMV US proteins. Thus, our data suggest that the gene products of HCMV have evolved complementary activities, comprising a strategy that allows the virus to evade the host immune response.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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HeLa and U373-MG astrocytoma cell lines were obtained from American Type Culture Collection (Manassas, VA) and cultured in DMEM (Life Technologies, Gaithersburg, MD) supplemented with 10% FBS (HyClone Laboratories, Logan, UT), 2 mM L-glutamine, 50 U/ml penicillin, and 50 µg/ml streptomycin. Human foreskin fibroblast (HFF) cells (passage 8–10) were used in this study. HFF cells were grown in DMEM supplemented with 10% FBS under 5% CO2 at 37°C. To establish stable cell lines expressing US2 or US11, we cloned each cDNA into the pcDNA3.1 mammalian expression vector (Invitrogen, Carlsbad, CA) and transfected the resulting constructs into U373-MG cells by the calcium phosphate precipitation method. Stable clones were selected by adding 0.5 mg/ml G418 (Life Technologies). Stable transfectants expressing tetracycline-inducible US3, US6, or ICP47 (the HSV immediate early protein, or TAP inhibitor) have been described previously (7, 8, 17).
Antibodies
mAb 10C7 (American Type Culture Collection) recognizes UL18. MHC
class I-specific antiserum K455 was raised against purified human class
I heterodimers with human 2m
(18). K455 recognizes H chain and
2m in both assembled and nonassembled forms.
mAb W6/32 recognizes only the complex of H chain and
2m. Normal mouse IgG was purchased from
Sigma-Aldrich (St. Louis, MO). Polyclonal antisera specific for US2
(anti-US2), US3 (anti-US3), US6 (anti-US6), and US11
(anti-US11) were raised against synthetic peptides corresponding to
the N-terminal portion of the proteins (7, 8).
Pulse-chase labeling and immunoprecipitation
Cells were starved for 30 min in medium lacking methionine,
labeled with 0.1 mCi/ml [35S]methionine
(TranS-label; NEN Life Science, Boston, MA) for 15 min and chased in
regular medium for the indicated times. After one wash with cold PBS,
the cells were lysed using 1% Nonidet P-40 (Sigma-Aldrich) in PBS or
1% digitonin in PBS for 30 min at 4°C. After this incubation,
protein G-Sepharose beads (Amersham Pharmacia Biotech, Piscataway, NJ)
were added to the lysates. The protein binding beads were then washed
four times with 0.1% Nonidet P-40 or 0.1% digitonin, and the proteins
were eluted by boiling in SDS sample buffer. Samples were separated by
10% SDS-PAGE. The gels were dried, exposed to BAS film, and analyzed
using the phosphor imaging system (BAS-2500; Fuji Film, Tokyo, Japan).
For endoglycosidase H treatment, the immunoprecipitates were digested
with 3 mU endoglycosidase H (Roche, Indianapolis, IN) for 16 h at
37°C in 50 mM NaOAc (pH 5.6), 0.3% SDS, and 150 mM -ME.
Viruses and viral infection
UL18 cDNA was provided by P. Bjorkman (California Institute of Technology, Pasadena, CA). Vaccinia virus recombinant expressing UL18 was produced by cloning cDNA encoding the respective gene behind the early/late vaccinia virus p7.5 promoter into a modified pSC11 plasmid as previously described (19), and plaque was purified three times in thymidine kinase-deficient 143B cells under bromodeoxyuridine selection (50 µg/ml). Cells were infected with recombinant vaccinia viruses at a multiplicity of infection of 10 for 1 h in 500 µl PBS supplemented with 10% BSA (Sigma-Aldrich) at 37°C. The AD169 strain of HCMV was used to infect HFF cells.
Flow cytometric analysis
The surface expression of UL18 and MHC class I molecules was determined by flow cytometry (FACSCalibur; BD Biosciences, Mountain View, CA). Cells (1 x 106) were washed twice with cold PBS containing 1% BSA and then incubated for 1 h at 4°C with either 10C7 for UL18 or W6/32 for MHC class I molecules. Normal mouse IgG was used as a negative control at each test. The cells were washed twice with cold PBS containing 1% BSA and then stained with FITC-conjugated goat anti-mouse IgG for 40 min. A total of 10,000 gated events were collected by the FACSCalibur cytometer and analyzed with CellQuest software (BD Biosciences).
RNA isolation and RT-PCR analysis
HFF cells were infected with the wild-type HCMV strain AD169 at a multiplicity of infection of 0.5. We used the RNeasy Mini kit according to the manufacturer’s instructions (Qiagen, Valencia, CA) to isolate total RNA from infected cells at the indicated time points. For RT-PCR, we used the SuperScript RT-PCR system (Life Technologies) with the following primers: GAPDH, 5'-ACCACCATGGAGAAGGCTGG; GAPDH, 3'-CTCAGTGTAGCCCAGGATGC; US2, 5'-GTGATGCCGATCTTCGAGA; US2, 3'-CAGTCCACAGTCACATACAC; US3, 5'-CCACCATGATGAGCGCGG; US3, 3'-GCAGACGGGCGCCC; US6, 5'-ATCCCGTCCGAACGATAGG; US6, 3'-TCGATTCGTATGTTATGCTGC; US11, 5'-GGTGTACTACCAGACGCTG and 3'-ATCATCAGCGTATACTGCG; UL18, 5'-ATAGCGAGCCTCAATGCAAT; and UL18, 3'-GTTAGCTGTCGGGTGATCA. An initial denaturation at 94°C for 5 min was followed by 40 cycles of denaturation at 94°C for 1 min, annealing at 60°C for 1 min, and extension at 72°C for 1 min, ending with a final extension at 72°C for 10 min.
Biotinylation of cell surface proteins
Biotinylation of cell surface proteins was performed essentially as previously described (20) with minor modifications. Cells were washed gently twice in ice-cold PBS. Cells were incubated with sulfo-NHS-biotin working solution (0.5 mg/ml; Pierce, Rockford, IL) with gentle shaking for 30 min at 4°C. After washing three times with PBS, cells were lysed in Nonidet P-40. After centrifugation at 10,000 x g for 15 min at 4°C, the supernatant was transferred to a new tube and the mAb 10C7 was added. Vials were rotated for 1 h at 4°C. Subsequently, 50 µl of 50% prewashed protein G-Sepharose (Amersham Pharmacia Biotech, Piscataway, NJ) was added, and the vials were rotated for a further 30 min at 4°C. After washing three times with PBS, bound proteins were eluted by boiling in SDS sample buffer, separated on SDS-PAGE, and transferred to an Immobilon-P membrane (Millipore, Bedford, MA). The membrane was incubated for 2 h in blocking buffer, followed by HRP-conjugated streptavidin for 3 h. Biotinylated surface proteins were visualized using ECL Western blotting reagent (Amersham Pharmacia Biotech).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Because down-regulation of UL18 by the US gene products could
render HCMV-infected cells susceptible to attack by NK cells, we
hypothesized that expression of the UL18 and US genes did not overlap.
To determine the times during HCMV infection that the UL18 and US genes
are expressed, we extracted RNA at various time points from AD169 (HCMV
wild-type)-infected HFF cells for RT-PCR analysis. We included GAPDH
primers as the internal PCR control. The results showed that US2 mRNA
expression was first detected 12 h postinfection but could not be
detected after 120 h postinfection (Fig. 1
). US3 mRNA was detected from 4–12 h
postinfection. US6 mRNA was expressed from 8–120 postinfection, and
the expression profile of US11 mRNA was similar to the pattern observed
for US6 mRNA. The UL18 mRNA was detected from 54 to at least 120 h
postinfection. Contrary to our hypothesis, the UL18 gene and the other
US genes, except US3, displayed a partially overlapping temporal
pattern of expression, suggesting that UL18 could potentially be
subjected to down-regulation mediated by the US2, US6, or US11 gene
product.
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Next, we determined whether the US gene products could
functionally mediate down-regulation of UL18. The US2 and US11 gene
products induce rapid export of the class I H chains out of the ER and
into the cytosol, where they are degraded by proteasomes; therefore,
US2 and US11 cause the down-regulation of MHC class I surface
expression in HCMV-infected cells (4, 5). To find out
whether HCMV US2 and US11 can down-regulate the surface expression of
UL18, we infected U373-MG cells expressing stably US2 or US11
(U373-MG-US2 and U373-MG-US11) and parental U373-MG cells with either a
recombinant, UL18-expressing vaccinia virus (vvUL18) or a wild-type
vaccinia virus (vvWT). To monitor cell surface expression of MHC class
I molecules and UL18, we used mAb W6/32 and 10C7 for flow cytometry.
Normal mouse IgG was used as a negative control. Although the UL18
protein was readily detected by immunoprecipitation in vvUL18-infected
cells, analysis by flow cytometry showed that low levels of UL18 were
expressed on the cell surface (Fig. 2A, c and
d), a finding that agrees with previous reports (16, 21). Because cell surface expression of UL18 is a prerequisite
for our study, we confirmed the cell surface expression of UL18 by
surface biotinylation and immunoprecipitation. Using the 10C7 mAb, we
could detect an 67-kDa biotinylated UL18 protein from the
vvUL18-infected cells, but not from the vvWT-infected cells (Fig. 2B, lanes 1 and 2, respectively). It
is noteworthy that the biotinylation of cell surface UL18 molecules was
also observed in the cells stably expressing US2, US3, US6, or US11
upon infection with vvUL18 (lanes 3–6). Control
experiments indicated that surface levels of MHC class I were equal
between parental U373-MG cells (uninfected) and vvWT-infected parental
U373-MG cells (Figs. 2Aa and
3Aa). As expected, the
expression of endogenous MHC class I molecules on the cell surface was
significantly reduced in US2- or US11-expressing cells (Figs. 2Ab and 3Ab). These results indicate that the
function of US2 or US11 for down-regulating MHC class I surface
expression was not altered by wild-type vaccinia virus gene products.
In contrast, UL18 surface expression was not affected by US2 or US11
(Figs. 2A and 3A, compare c and
d).
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C and
3B, lanes 5 and 6). In
line with the previous report (22), nearly all MHC
class I molecules were degraded at the 30 min chase point in
U373-MG-US2- and -US11 cells (Figs. 2C and 3B,
lane 8). When cells were infected with vvUL18, the UL18 gene
product of Mr 67 kDa was
immunoprecipitated by 10C7 mAb (Figs. 2C and 3B,
lanes 1–4). The molecular mass of UL18 was
reduced to 39 kDa by endoglycosidase H treatment (data not shown).
Together with the facts that UL18 has a predicted molecular mass of 39
kDa, and UL18 has 13 potential N-glycosylation sites, these
findings indicate that UL18 is immediately glycosylated in the ER as it
is synthesized. Contrary to the results obtained for MHC class I
molecules, neither US2 nor US11 affected the fate of UL18. That is, no
US2- or US11-associated degradation of UL18 was observed (Figs. 2C and 3B). Immunoprecipitation with anti-US2
and anti-US11 demonstrated expression of these molecules in cells
(Figs. 2C and 3B, lanes 11
and 12). The results suggest that UL18 possesses
characteristics that protect it from US2- or US11-associated
degradation. US3 does not down-regulate the surface expression of UL18
US3 expression causes MHC class I molecules to accumulate in the
ER by preventing the transport of MHC class I molecules to the cell
surface (6, 7). To analyze whether US3 can also
down-regulate the surface expression of UL18, we infected HeLa cells
that expressed the tetracycline-inducible US3 (7) with
either vvUL18 or vvWT. The expression of US3 was induced by removal of
tetracycline from the culture medium for 24 h before infection.
The cell surface expression of MHC class I molecules and UL18 was
monitored by flow cytometry with mAb W6/32 and 10C7. Whereas a
reduction in MHC class I surface expression was observed upon
expression of US3, the expression of US3 did not exert an effect on the
surface expression of UL18 molecules (Fig. 4A).
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B,
lanes 4 and 1, respectively). With the
K455 Ab, US3 protein coimmunoprecipitated with the MHC class I
molecules (lane 5). In contrast, we did
not observe coimunoprecipitation between US3 and UL18 in both
anti-US3 and 10C7 immunoprecipitates (lanes
4 and 6) under our experimental conditions,
implying that US3 does not bind to UL18. It appears that the 10C7 Ab
does not recognize the complexed form of UL18 with
2m, as does K455. This may be the reason for
the lack of coimmunoprecipitation. Another possibility is that these
Abs may not able to recognize a US3/UL18 complex because their epitopes
are involved in binding. Cell surface expression of UL18 is dependent on TAP, but is not influenced by US6
The HCMV US6 gene product prevents peptide loading of the MHC
class I molecules by inhibiting TAP-mediated peptide translocation into
the ER and consequently results in down-regulation of MHC class I
molecules at the cell surface (8, 9). To examine whether
US6 can down-regulate the surface expression of UL18, we infected HeLa
cells that expressed the tetracycline-inducible US6 (8)
with either vvUL18 or vvWT. In uninduced cells, the surface level of
MHC class I molecules was not affected in the presence of vvWT (Fig. 5Aa). When US6 expression was
induced, down-regulation in surface expression of endogenous MHC class
I molecules was evident in the cells (Fig. 5Ab). These
results indicate that vvWT does not affect either the surface
expression of MHC class I or the function of US6 to interfere with the
surface expression of MHC class I molecules. Unlike MHC class I
molecules, surface expression of UL18 was not affected by US6 (Fig. 5A, compare c and d). This might be
due to competition for TAP between US6 and UL18 or to an intrinsic
property of UL18 for TAP independence.
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B,
b and d, respectively). These results suggest
that the surface expression of UL18 is dependent on TAP activity, but
TAP inhibition by US6 is somehow disrupted in the presence of
UL18. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In contrast to the other US-encoded genes, US3 transcripts were
expressed at a different window of time from UL18. US3 mRNA was
detected 4–12 h postinfection, confirming the immediate early nature
of this gene, whereas the UL18 transcript was expressed beginning at
54 h postinfection and thereafter. US3 proteins are short-lived
and present only during the first hours of infection (26).
US3 and UL18 proteins are thus unlikely to coexist during infection.
Besides this temporal reciprocal expression relationship, US3 did not
bind UL18 molecules and thus functionally could not prevent them from
leaving the ER. We have recently reported that US3 is capable of
binding HLA-G, a nonclassical MHC class I molecule, as well as HLA-A,
-B, and -C alleles (27), suggesting that US3 has a broad
specificity for binding MHC class I alleles. Although we do not know
which structure of the MHC class I molecules is recognized by US3, the
demonstrated lack of coimmunoprecipitation of UL18 with US3 prompts
consideration of structural attributes that might disallow either
direct interaction or interactions via a molecular intermediate.
Despite their amino acid sequence homology to MHC class I sequences,
UL18 molecules possess a number of features that are dissimilar from
those of classical class I molecules. In contrast to only one
glycosylation site in MHC class I molecules, UL18 is heavily
glycosylated, containing 13 potential N-linked glycosylation
sites (13) that account for the different molecular mass
of UL18 and the MHC class I H chain (
Figs. 2–4). It is possible that
the carbohydrate moieties of UL18 glycoprotein interfere with the
interaction between UL18 and US3. Likewise, the same interpretation can
be made for the lack of binding of US2 and US11 to UL18. The analysis
reported in this work provides a starting point for a more precise
delineation of the elements of class I molecules that are recognized by
the US proteins.
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The functional role of UL18 as an inhibitor of NK cell cytotoxicity
remains controversial. 721.221 cells stably transfected with UL18 but
selected for expression of 2m were shown to be
resistant to NK cell lysis (21). In contrast to this,
transient expression of UL18 in human, primate, and rodent cell lines
results in enhanced killing by NK cells (16). The apparent
contradictory results of these studies might reflect the complexity of
activating and inhibitory signals that control NK cell function. Given
the facts that leukocyte Ig-like receptor-1, a ligand for UL18,
binds UL18 with a 1000-fold higher affinity than host MHC class I
molecules (31) and that surface expression of UL18 is not
subjected to US protein-mediated down-regulation, however, it seems
obvious that cell surface UL18 potentially plays a role in immune
evasion. UL18 probably evolved from a host cell MHC class I gene
acquired by HCMV at some point during its evolution with its human host
(32). While UL18 has retained most of the structural
properties of class I molecules, the unique resistance of UL18 to
US-associated down-regulation indicates that UL18 possesses
characteristics of structure and/or processing that distinguish it from
other classical MHC class I molecules. The information presented in
this study will assist in future studies aimed at deciphering the exact
role of UL18 in immune recognition of HCMV-infected target cells and is
likely to enhance understanding of the interplay between viruses and
the immune system.
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Acknowledgments |
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Footnotes |
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2 B.P. and H.O. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Kwangseog Ahn, Graduate School of Biotechnology, Korea University, 1 5-Ga, Anam-Dong, Sungbuk-Gu, Seoul 136-701, Korea. E-mail address: ksahn{at}korea.ac.kr
4 Abbreviations used in this paper: HCMV, human CMV; 2m, 2-microglobulin; UL18, unique long region protein 18; US, unique short region protein; ER, endoplasmic reticulum; HFF, human foreskin fibroblast; vvUL18, UL18-expressing vaccinia virus; vvWT, wild-type vaccinia virus.
Received for publication September 20, 2001. Accepted for publication January 25, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2 microglobulin. Nature 347:770.[Medline]
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