| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Graduate School of Biotechnology, Korea University, Seoul, Korea;
Department of Microbiology and Immunology, Catholic University Medical College, Seoul, Korea; and
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98104
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Although reduced expression of HLA-G is associated with some abnormalities during pregnancy, its function at the maternal-fetal interface still needs to be investigated. One recognized role of NK cells is to eliminate cells that have lost class I MHC surface expression because of events like malignant transformation or viral infection. There is mounting evidence that HLA-G protects trophoblast cells from being recognized by NK cells (5, 6). It has been shown with a class I MHC-negative B lymphoblastoid cell line 721.221 that expression of HLA-G protected these otherwise susceptible target cells from NK-mediated cytotoxicity (7). Several studies have revealed that HLA-C molecules are the dominant ligands that prevent the killing of a target by NK cells (8, 9). But it is not yet known to what extent HLA-G or HLA-C are involved in the protection of trophoblast from NK cell attack in vivo. The HLA-C molecules may have a complementary purpose or be a redundant counterpart of HLA-G in the mechanism that lets trophoblast cells evade NK-mediated lysis.
Human CMV (HCMV)3
(10), a 
-herpesvirus, exists ubiquitously in human
populations worldwide, with a primary infection being followed by
lifelong persistence of the virus in the host. HCMV contributes in
particular to the high morbidity and mortality of immunocompromised
patients, most notably organ transplant recipients and AIDS patients,
as well as infants infected in utero where it infects the trophoblast
(11). Thus, an epidemiological correlation between HCMV
infection and spontaneous fetal loss has been reported
(12). However, to date, a mechanism that would explain
this linkage remained to be discovered.
HCMV has evolved multiple strategies in causing down-regulation of HLA-A and -B expression on the surface of cells after they have become infected with the virus (13). At present, four different gene products, US2, US3, US6, and US11, have been identified that can independently reduce 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 they are degraded by proteasomes (14, 15). 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 (16, 17). Furthermore, US6 prevents peptide loading of the class I MHC 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 (18, 19, 20).
The sequence similarities between HLA-G and -C and HLA-A and -B
(21) along with the molecules’ ability to form trimeric
complexes with 2-microglobulin
(2m) and peptides (22)
suggests that the US proteins may act on the placenta-specific
class I molecules HLA-G and -C in a manner that is analogous to their
action on their classical counterparts. The down-regulation of
trophoblast class I Ag presentation on the cell surface upon HCMV
infection may expose the cells to NK-mediated lysis, which in turn may
cause the spontaneous fetal abortion. However, recent findings by
Schust et al. (23) argue against such a scenario. These
researchers showed that, unlike the classical class I molecules, both
HLA-G and HLA-C are fully resistant to rapid degradation associated
with US2 and US11 HCMV gene expression. However, these data do not
support the conclusion that there is a general resistance of
trophoblast cells to class I down-regulation upon HCMV infection. The
possibility remained that US3 or US6 or other unidentified molecules
could be the cause of the down-regulation of class I MHC surface
expression on the trophoblast.
We found in our study described here that both US3 and US6 can independently down-regulate HLA-G and HLA-C expressions on the cell surface. In a manner similar to their classical counterparts, both trophoblast class I molecules are bound by US3 and sequestered inside the ER, while the US6 gene product inhibits peptide transport and thus also down-regulates surface HLA-G and HLA-C expression. In so far, our data suggest that down-regulation of HLA-G and HLA-C may be one of the mechanisms involved in spontaneous abortions in HCMV infection.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The trophoblast-derived choriocarcinoma cell line JEG-3 and mouse NIH3T3 fibroblasts were obtained from the American Type Culture Collection (Manassas, VA) and cultured in MEM (Life Technologies, Rockville, MD) supplemented with 10% FBS (HyClone, Logan, UT), penicillin (50 U/ml), and streptomycin (50 µg/ml). The lymphoblastoid cell line (LCL) 721.221 transfectants stably expressing HLA-G1 molecules were generated as described previously (22) and maintained in RPMI 1640 medium (Life Technologies) containing 10% FBS, 2 mM glutamine, penicillin (50 U/ml), and streptomycin (50 µg/ml).
Constructs and transfection
The cloning of cDNAs for US2, US3, US6, US11, and ICP47 have been described (16, 18, 24). The cDNA coding for human CD4 was kindly provided by Dr. Y. Yang (R. W. Johnson Pharmaceutical Research Institute, San Diego, CA). Each cDNA was subcloned into the mammalian expression vector pUHD10.1 (25), and the resulting constructs were transfected into cells by the calcium phosphate precipitation method. If necessary, the cells were cotransfected with a plasmid conferring ouabain resistance (18), and the transfectants were enriched after being exposed to ouabain for 12 h before analysis.
Viruses and viral infection
Vaccinia virus (vv) recombinants expressing US3 and US6 were generated by homologous recombination essentially as described (26) and plaque purified three times in thymidine kinase-deficient 143B cells under bromodeoxyuridine selection (50 µg/ml). JEG-3 cells were infected with recombinant vaccinia virus at a multiplicity of infection of 25 for 1 h in 500 µl of PBS supplemented with 10% BSA (Sigma, St. Louis, MO) at 37°C. LCL 721.221 cells were infected with vaccinia virus at a multiplicity of infection of 50 for 2 h in 1 ml RPMI 1640 medium at 37°C.
Abs
MHC class I-specific antiserum K455 was raised against purified
human class I heterodimers with human 2m
(27). K455 recognizes H chain and
2m in both assembled and nonassembled forms.
Monoclonal Ab W6/32 recognizes only the complex of H chain and
2m, and mAb OKT4 recognizes human CD4. The
monoclonal 87G Ab reacts specifically with HLA-G (22).
Polyclonal antisera detecting US3 and US6 were raised against synthetic
peptides corresponding to the luminal
NH2-terminal portion of the proteins (16, 18).
Flow cytometric analysis
The expression of class I MHC glycoproteins on the membrane was determined by flow cytometry (FACScalibur; Becton Dickinson, Mountain View, CA) after indirect immunofluorescence staining using anti-class I (W6/32) mAb and FITC-conjugated goat anti-mouse Ab (Sigma). A total of 10,000 gated events were collected by the FACScalibur and analyzed using the CellQuest software (Becton Dickinson).
Metabolic labeling and immunoprecipitation
Cells were methionine-starved for 30 min in a
methionine-deficient medium before pulse-labeling for 30 min using 0.1
mCi/ml of [35S]methionine (TranS-label;
Amersham, Arlington Heights, IL). The label was chased at various time
points with MEM containing 10% FBS. After one wash with cold PBS, the
cells were lysed using 1% Nonidet P-40 (Sigma) in PBS or 1% digitonin
in PBS for 30 min at 4°C. After this incubation, protein A-Sepharose
beads (Pharmacia, Uppsala, Sweden) 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 eluted by boiling in SDS
sample buffer. All immunoprecipitates were electrophoresed in gradient
SDS-polyacrylamide gels. The gels were dried, exposed to BAS film,
and analyzed using the Phosphor Imaging System (BAS-2500, Fuji
Film Company). For endoglycosidase H (Endo H) treatment, the
immunoprecipitates were digested with 3 mU of Endo H (Boehringer
Mannheim, Mannheim, Germany) for 16 h at 37°C in 50 mM NaOAc, pH
5.6, 0.3% SDS, 150 mM -ME.
Peptide transport assay
Transport assays were performed as previously described (18). Briefly, the JEG-3 cells were trypsinized and washed twice with transport buffer (130 mM KCl, 10 mM NaCl, 1 mM CaCl2, 2 mM EGTA, 2 mM MgCl2, 5 mM HEPES, pH 7.3 adjusted with KOH) at 4°C and then permeabilized (107 cells/ml) by incubation in transport buffer containing 1 U/ml streptolysin-O for 20 min at 37°C. The permeabilized cells (106 cells/sample) were then incubated for 10 min at 37°C in 5 µM of a FITC-conjugated peptide (RYNATGRL) in transport buffer containing 1 mM DTT and 10 mM ATP. Following lysis in 1% Nonidet P-40, the glycosylated peptide fraction was isolated with Con A-Sepharose beads (Pharmacia) and fluorescence (excitation, 485 nm; emission, 530 nm) on the peptides eluted from Con A was measured in a fluorescence reader (HTS 7000 Bio Assay Reader; Perkin-Elmer, Norwalk, CT).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Analyses of a series of HCMV deletion mutants identified a 7-kb
unique short (US) region as being required for class I H chain
down-regulation in HCMV-infected cells (28). Among the
genes within this region, four of the encoded proteins, US2, US3, US6,
and US11, are able to reduce classical class I expression on the cell
surface when individually expressed (14, 15, 16, 17, 19, 20). To
determine whether these gene products also affect the trophoblast class
I species HLA-G and HLA-C, we tried to express each US cDNA separately
in cells of a tumor cell line of extra-embryonic origin, JEG-3.
However, we failed to establish stable US transfectants in JEG-3,
because the prolonged expression (>1 wk) of US protein resulted in
cell death. To circumvent this low efficiency of transient
transfection, we cotransfected JEG cells with US cDNA and a plasmid
conferring ouabain resistance (18). The transfectants
became enriched after being exposed to ouabain for 12 h and then
cultured for 72 h. The surface expression of trophoblast class I
molecules was monitored by flow cytometry using mAb W6/32. A specific
reduction in class I MHC surface expression was observed in cells
transfected with US3 and US6 (Fig. 1
A), whereas the surface
expression of cotransfected CD4 was not affected (Fig. 1B).
This kind of reduction was similar to the reduction seen in
transfectants expressing the TAP inhibitor ICP47 of HSV-1 (24, 29). In contrast, neither US2 nor US11 expression had an effect
on the surface expression of trophoblast class I molecules, which is in
agreement with the recent findings by Schust et al.
(23).
|
The choriocarcinoma cell line JEG-3 expresses HLA-G and HLA-Cw4, both of which are recognized by W6/32 (30). To further delineate the substrate specificity of US3 and US6 for trophoblast class I molecules and to evaluate potentially unique characteristics of the trophoblast class I molecules, we examined the effects of US3 and US6 on the intracellular transport and processing of HLA-G and HLA-C. In line with the previous finding by Rosenthal et al. (31), JEG-3 cells were nonpermissive for HCMV infection in our experimental conditions as well. Therefore, JEG-3 cells were infected either with a recombinant vaccinia virus driving the expression of the HCMV US3 (vvUS3) or with a recombinant vaccinia virus driving the expression of the HCMV US6 (vvUS6). The proteins in the infected cells were then labeled, chased for various times, detergent extracted, and finally treated for immunoprecipitation with W6/32. Before analysis by SDS-PAGE, half of each sample was treated with Endo H.
The pulse-chase analysis showed that similar amounts of W6/32-reactive
class I molecules were synthesized during the 30-min labeling period
(Fig. 2A). Interestingly, the
intracellular transport rate of HLA-G, as analyzed by Endo H digestion,
was unusually slow, and we consistently observed that some of the HLA-G
molecules remained in the ER even after the 6-h chase point (Fig. 2A, lane 6). In contrast, all HLA-C molecules
traveled through the Golgi within 30 min of chase (data not shown),
which is typical for the kinetics of HLA-A and HLA-B transport
(18). In cells infected with vvUS3, the intracellular
transport of trophoblast class I species, both HLA-G and HLA-C, was
completely inhibited, although their synthesis and glycosylation was
not affected (Fig. 2A). Similar experiments with vvUS6
revealed that the expression of US6 also inhibited intracellular
transport of HLA-G and HLA-C in JEG-3 cells (Fig. 2B). In
contrast, neither the expression of US3 nor the expression of US6
affected the processing of transferrin receptors (data not shown),
indicating that the effects of US3 and US6 were specific for the class
I molecules. Immunoprecipitation with appropriate Abs revealed that the
JEG-3 cells infected either with vvUS3 or with vvUS6 did express US3
and US6, respectively (Fig. 2C). In comparison to the
vvUS3-infected cells, both HLA-G and HLA-C molecules in the
vvUS6-infected cells were being degraded rather rapidly during the
chase. We could not detect HLA-G and HLA-C molecules at the 360-min
time point. This finding was in agreement with previous studies by
Hughes et al. (32), where it was shown that
peptide-deficient class I-2m heterodimers
induced by the TAP inhibitor ICP47 of HSV-1 were moved from the ER to
the cytosol, where they were deglycosylated and subsequently degraded
by proteasomes. As in the case of the misfolded class I proteins
induced by ICP47, the peptide-deficient class I molecules made as a
consequence of TAP blocking by US6 appeared to produce a similar
result. Therefore, we concluded that the HCMV US3 and US6 gene products
had a capability that prevented trophoblast class I products from
leaving the ER.
|
To determine whether the ER retention of trophoblast class I
molecules caused by US3 or US6 is limited to specific cell types and
whether the distinct kinetics of HLA-G, in particular, are
characteristic of the placenta cell type, we performed the identical
experiments as conducted with JEG-3 cells using HLA-G-expressing LCL
721.221 cells (HLA-G/221). In wild-type vaccinia virus-infected cells
(vvWT), the overall kinetics of the transport rate were similar to
those observed in the JEG-3 cells (Fig. 3). The results suggest that the slow
maturation and movement of HLA-G along the Ag presentation pathway is
attributable to its own unique characteristics and is not cell type
specific.
|
US3 binds directly to HLA-G and HLA-C
The facts that US3 is a type I transmembrane glycoprotein
localized in the ER (17) and that the trophoblast class I
molecules of the vvUS3-infected cells were sensitive to Endo H
digestion prompted us to look for a possible direct association between
US3 and trophoblast class I molecules. JEG-3 cells were infected either
with vvUS3 or with vvWT and metabolically labeled, after which they
were lysed with digitonin buffer. As shown in Fig. 4, both HLA-G and HLA-C could be
immunoprecipitated from the digitonin extract with anti-H chain
antiserum (K455) (Fig. 4A, lanes 2 and
5), but not with anti-US3 antiserum (Fig. 4A,
lanes 1 and 4). Using the K455 Ab, a 22-kDa
protein coprecipitated with the class I molecules from the
vvUS3-infected cells, but not from the vvWT-infected cells (Fig. 4A, compare lane 5 with lane
2). This 22-kDa protein comigrated with the protein band
detected by the anti-US3 antiserum (Fig. 4A, lane
4, for the control see lane 1). Therefore, these data
confirm the identity of the coprecipitated protein as being
US3.
|
2m (Fig. 4
A, lane 3).
However, in extracts of vvUS3-infected JEG-3 cells, the 87G
immunoprecipitate contained HLA-G, 2m and US3
(Fig. 4A, lane 6). This indicates physical
association of these three components. To then further look for a
specific association between HLA-C and US3, any residual HLA-G
molecules that could have remained in the supernatant after the first
immunoprecipitation (Fig. 4A, lanes 3 and
6) were extracted by two more rounds of immunoprecipitation
with excess amounts of 87G Ab. The resultant supernatant was then
subjected to immunoprecipitation with anti-HC K455 Ab. For both
vvWT- and vvUS3-infected cells, no more HLA-G was detectable (Fig. 4A, lanes 7 and 8), whereas the amount
of HLA-C material recovered was still similar to that obtained by
"direct immunoprecipitation" of the untreated, original cell
extract (compare lanes 2 and 5 with lanes
7 and 8, respectively). Under these conditions, US3
could be coimmunoprecipitated from lysates of vvUS3- (lane
8) and not from vvWT-infected cells (lane 7).
Therefore, the results clearly indicate that US3 associates physically
with either of the class 1 proteins, HLA-G and HLA-C, retaining them in
the ER.
NK cells are grouped into two types, namely NK1 and NK2
(8), depending on their ability to discriminate between
two groups of HLA-C allotypes. It has been shown that the product of
the HLA-C locus in JEG-3 cells is HLA-Cw*0401 (30) and
that it can inhibit NK1 cells. To see whether US3 exhibited some
allotype specificity for products of the HLA-C locus, we cotransfected
mouse NIH3T3 cells with the US3 cDNA and HLA-Cw*0304 cDNA, the product
of which is known to inhibit NK2 cells. The physical association
between these gene products was then examined by coimmunoprecipitation.
Both W6/32 and K455 immunoprecipitates from digitonin lysates contained
HLA-Cw*0304, mouse 2m, and US3 (Fig. 4B, lane 1, 2, and 3,
respectively). The binding of US3 to HLA-Cw*0304 was also observed in
the reciprocal experiment in which US3 was immunoprecipitated with
anti-US3 Ab (Fig. 4B, lane 3). Neither W6/32
nor K455 showed cross-reactivity with endogenous mouse class I
molecules (data not shown). Despite the differences in the deduced
amino acid sequence of the two HLA-C allotypes, it is unlikely that US3
exhibits HLA-C allotype specificity. It is much more likely that it
recognizes conserved regions in the HLA-C molecules. In addition, these
results show that MHC molecules are altered in their expression by the
HCMV US3 gene product in different species of cells.
Peptide translocation by TAP is inhibited by US6 in JEG-3 cells
Using a peptide translocation assay (33), we and
others have shown that HCMV US6 inhibited TAP-mediated peptide
translocation in adherent cells (18, 19, 20) and that the
peptide translocation in JEG-3 cells is readily measurable
(34). To determine whether the impaired maturation of the
trophoblast class I molecules in vvUS6-infected cells reflects a lack
of available class I binding peptide in the lumen of the ER, we
directly examined the effect of US6 expression on peptide translocation
by TAP in JEG-3 cells. The rate of peptide translocation was compared
between vvUS6- and control-infected cells (Fig. 5). No inhibition in TAP-mediated peptide
translocation, as assessed by the glycosylation of FITC-conjugated
peptides, was observed in both vvWT- and vvUS3-infected cells. In
contrast, all peptide transport activity was completely abolished in
vvUS6-infected cells, to an extent that is comparable to the one
observed when ATP is removed. We conclude that the impaired transport
of trophoblast class I molecules is an event that occurs downstream TAP
inhibition by US6. Therefore, these results reflect the importance of a
functional TAP for proper assembly and trafficking of nonclassical
class I molecules as well as classical class I molecules.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Our present study has revealed that the HCMV US3 gene product binds totrophoblast class I molecules, retaining them in the ER, and that the HCMV US6 gene product inhibits TAP-mediated peptide translocation from the cytosol to the ER. Despite differences in the mechanisms of these US protein activities, the consequences are the same: a decrease in class I Ag presentation on the cell surface. Our results also indicate that the ER retention of the class I MHC molecules mediated by the HCMV US3 gene product is neither cell type nor allotype specific. In contrast to US3 and US6, the expression of US2 or US11 does not have an effect on the expression of class I molecules on the surface trophoblast cells. This is in agreement with previous findings by Schust et al. (23). These researchers showed that, in contrast to previous results pertaining to human classical class I molecules, both HLA-G and HLA-C are completely resistant to the rapid degradation mediated by the HCMV US2 and US11 gene products. Initially, the possibility had been raised that trophoblast class I molecules might have unique characteristics that allowed them to escape from the class I down-regulation generally associated with HCMV infection. However, this seems not the case, because our data show that the US3 and US6 gene products of HCMV can also interrupt the surface expression of HLA-G and HLA-C, although the existence of still another gene product affecting the down-regulation of the trophoblast class I species cannot be excluded at this time. Therefore, our observations provide first evidence of a possible molecular mechanism underlying HCMV-related spontaneous pregnancy loss.
There must be several reasons why HCMV developed multiple mechanisms to prevent MHC class I presentation. One possible explanations could be that the selective pressure forcing the virus to cope with the presentation of a variety of MHC class I alleles may have favored diversification of the HCMV US genes and their functions. Down-regulation of the surface expression of the class I MHC molecules may be a mechanism by which the virus can escape the host’s CTL response, although there may still remain a potential risk, because the infected cell itself may become vulnerable to NK attack. Differential regulation of class I MHC molecules may thus allow virus-infected cells to avoid NK-mediated lysis. For instance, HIV-1 selectively down-regulates HLA-A and HLA-B but does not significantly affect HLA-C or HLA-E (35). The adenovirus E3/19K protein binds more tightly to certain human class I MHC alleles during their retention in the ER than to others (36). Pseudo-rabies virus infection results in decreased expression of the Dk allele and an increased Kk allele expression in murine L929 cells (37). Furthermore, the US2 and US11 gene products exhibit substrate specificities for murine class I molecules, albeit they do not represent natural substrates for HCMV (38). These differential regulatory mechanisms may create a balance of conditions optimal for the escape of viruses from CTL and for protection against NK cells.
Peptide translocation happens independently of class I MHC molecules, because TAP inhibition occurs upstream of the class I MHC transport. Therefore, it is unlikely that HCMV US6 should exhibit class I substrate specificity, and we predict that HCMV US6 would also influence the surface expression of the HLA-E, which is nonclassical class I MHC molecule expressed in cytotrophoblast cells (39). However, we do not rule out the possibility that even in the presence of US6, a certain portion of class I MHC molecules, albeit not detectable in our assay systems, might acquire peptides via a TAP-independent peptide transport (40) before reaching the cell surface, where they could then play a role in inhibiting NK cell lysis. It seems that the ER retention associated with the HCMV US3 gene product could be a more general characteristic of all HLA locus products, because the US3 protein binds to a broad spectrum of HLA-A and HLA-B allotypes with no particular preference (S. Lee and K. Ahn, manuscript in preparation). This is also supported by our finding that US3 did not differentially bind to either HLA-Cw*0401 or HLA-Cw*0304, which are the common inhibitory receptors for NK1 and NK2 cells, respectively. Furthermore, our data suggest that HCMV US3 has evolved to recognize both classical and nonclassical class I molecules.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Kwangseog Ahn, Graduate School of Biotechnology, Korea University, 1, 5-ka, Anam-dong, Sungbuk-ku, Seoul 136-701, Korea. E-mail address:
3 Abbreviations used in this paper: HCMV, human CMV; ER, endoplasmic reticulum; 2m, 2-microglobulin; LCL, lymphoblastoid cell line; Endo H, endoglycosidase H; US, unique sequence; vv, vaccinia virus; WT, wild type.
Received for publication September 8, 1999. Accepted for publication October 26, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  G. Roder, L. Geironson, I. Bressendorff, and K. Paulsson Viral Proteins Interfering with Antigen Presentation Target the Major Histocompatibility Complex Class I Peptide-Loading Complex J. Virol., September 1, 2008; 82(17): 8246 - 8252. [Full Text] [PDF]
|
|
|
|
|
|
M. Lafon, C. Prehaud, F. Megret, M. Lafage, G. Mouillot, M. Roa, P. Moreau, N. Rouas-Freiss, and E. D. Carosella Modulation of HLA-G Expression in Human Neural Cells after Neurotropic Viral Infections J. Virol., December 15, 2005; 79(24): 15226 - 15237. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. D. Kopcow, D. S. J. Allan, X. Chen, B. Rybalov, M. M. Andzelm, B. Ge, and J. L. Strominger Human decidual NK cells form immature activating synapses and are not cytotoxic PNAS, October 25, 2005; 102(43): 15563 - 15568. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Leis, M. Marschall, and T. Stamminger Downregulation of the cellular adhesion molecule Thy-1 (CD90) by cytomegalovirus infection of human fibroblasts J. Gen. Virol., July 1, 2004; 85(7): 1995 - 2000. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. T. Barel, M. Ressing, N. Pizzato, D. van Leeuwen, P. Le Bouteiller, F. Lenfant, and E. J. H. J. Wiertz Human Cytomegalovirus-Encoded US2 Differentially Affects Surface Expression of MHC Class I Locus Products and Targets Membrane-Bound, but Not Soluble HLA-G1 for Degradation J. Immunol., December 15, 2003; 171(12): 6757 - 6765. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. R. Hegde and D. C. Johnson Human Cytomegalovirus US2 Causes Similar Effects on Both Major Histocompatibility Complex Class I and II Proteins in Epithelial and Glial Cells J. Virol., September 1, 2003; 77(17): 9287 - 9294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Tomescu, W. K. Law, and D. H. Kedes Surface Downregulation of Major Histocompatibility Complex Class I, PE-CAM, and ICAM-1 following De Novo Infection of Endothelial Cells with Kaposi's Sarcoma-Associated Herpesvirus J. Virol., September 1, 2003; 77(17): 9669 - 9684. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Terauchi, H. Koi, C. Hayano, N. Toyama-Sorimachi, H. Karasuyama, Y. Yamanashi, T. Aso, and M. Shirakata Placental Extravillous Cytotrophoblasts Persistently Express Class I Major Histocompatibility Complex Molecules after Human Cytomegalovirus Infection J. Virol., August 1, 2003; 77(15): 8187 - 8195. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Baillie, D. A. Sahlender, and J. H. Sinclair Human Cytomegalovirus Infection Inhibits Tumor Necrosis Factor Alpha (TNF-{alpha}) Signaling by Targeting the 55-Kilodalton TNF-{alpha} Receptor J. Virol., June 15, 2003; 77(12): 7007 - 7016. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Odeberg, H. Browne, S. Metkar, C. J. Froelich, L. Branden, D. Cosman, and C. Soderberg-Naucler The Human Cytomegalovirus Protein UL16 Mediates Increased Resistance to Natural Killer Cell Cytotoxicity through Resistance to Cytolytic Proteins J. Virol., April 15, 2003; 77(8): 4539 - 4545. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Park and K. Ahn An Essential Function of Tapasin in Quality Control of HLA-G Molecules J. Biol. Chem., April 11, 2003; 278(16): 14337 - 14345. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Park, S. Lee, E. Kim, and K. Ahn A Single Polymorphic Residue Within the Peptide-Binding Cleft of MHC Class I Molecules Determines Spectrum of Tapasin Dependence J. Immunol., January 15, 2003; 170(2): 961 - 968. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Fairley, J. Baillie, M. Bain, and J. H. Sinclair Human cytomegalovirus infection inhibits epidermal growth factor (EGF) signalling by targeting EGF receptors J. Gen. Virol., November 1, 2002; 83(11): 2803 - 2810. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. R. Hegde, R. A. Tomazin, T. W. Wisner, C. Dunn, J. M. Boname, D. M. Lewinsohn, and D. C. Johnson Inhibition of HLA-DR Assembly, Transport, and Loading by Human Cytomegalovirus Glycoprotein US3: a Novel Mechanism for Evading Major Histocompatibility Complex Class II Antigen Presentation J. Virol., October 2, 2002; 76(21): 10929 - 10941. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Park, H. Oh, S. Lee, Y. Song, J. Shin, Y. C. Sung, S.-Y. Hwang, and K. Ahn The MHC Class I Homolog of Human Cytomegalovirus Is Resistant to Down-Regulation Mediated by the Unique Short Region Protein (US)2, US3, US6, and US11 Gene Products J. Immunol., April 1, 2002; 168(7): 3464 - 3469. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. E. Gewurz, E. W. Wang, D. Tortorella, D. J. Schust, and H. L. Ploegh Human Cytomegalovirus US2 Endoplasmic Reticulum-Lumenal Domain Dictates Association with Major Histocompatibility Complex Class I in a Locus-Specific Manner J. Virol., June 1, 2001; 75(11): 5197 - 5204. [Abstract] [Full Text]
|
|
|
|
|
|
B. Riteau, N. Rouas-Freiss, C. Menier, P. Paul, J. Dausset, and E. D. Carosella HLA-G2, -G3, and -G4 Isoforms Expressed as Nonmature Cell Surface Glycoproteins Inhibit NK and Antigen-Specific CTL Cytolysis J. Immunol., April 15, 2001; 166(8): 5018 - 5026. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Riteau, C. Menier, I. Khalil-Daher, S. Martinozzi, M. Pla, J. Dausset, E. D. Carosella, and N. Rouas-Freiss HLA-G1 co-expression boosts the HLA class I-mediated NK lysis inhibition Int. Immunol., February 1, 2001; 13(2): 193 - 201. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Lee, J. Yoon, B. Park, Y. Jun, M. Jin, H. C. Sung, I.-H. Kim, S. Kang, E.-J. Choi, B. Y. Ahn, et al. Structural and Functional Dissection of Human Cytomegalovirus US3 in Binding Major Histocompatibility Complex Class I Molecules J. Virol., December 1, 2000; 74(23): 11262 - 11269. [Abstract] [Full Text]
|
|
|
|
|
|
S. Lefebvre, S. Berrih-Aknin, F. Adrian, P. Moreau, S. Poea, L. Gourand, J. Dausset, E. D. Carosella, and P. Paul A Specific Interferon (IFN)-stimulated Response Element of the Distal HLA-G Promoter Binds IFN-regulatory Factor 1 and Mediates Enhancement of This Nonclassical Class I Gene by IFN-beta J. Biol. Chem., February 23, 2001; 276(9): 6133 - 6139. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
). No ATP was added for the control (
). Results
are presented as means of duplicate experiments.