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Departments of
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Immunology and
Molecular Biology, Division of Virology, The Scripps Research Institute, La Jolla, CA 92037
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It is well known that CMV infection results in immunodepression
(reviewed in Refs. 1 and 2). Both HCMV and MCMV employ many diverse
strategies to avoid detection by the host immune system. Among these
strategies is the ability to interfere with expression of MHC class I
proteins. A number of different molecular mechanisms, involving
specific viral gene products, have been characterized for both HCMV and
MCMV (3, 4, 5, 6). More recently, several groups have also shown that CMV can
cause decreased expression of MHC class II proteins, by more indirect
mechanisms (7, 8, 9). It has been reported that HCMV inhibits
IFN--induced MHC class II expression in endothelial cells via
induction of IFN-ß (7). HCMV can also interfere with class II on
alveolar epithelial cells (8). High doses of MCMV can inhibit class II
expression on macrophages from SCID mice, due partly to the induction
of IFN-ß (9). MCMV and HCMV can impair IFN--induced MHC class II
up-regulation, by blocking the action of the IFN- by both
IFN-
/ß-independent mechanisms (10) and disruption of the Jak/Stat
signaling pathway (11).
While other studies have investigated the effect of MCMV infection on
the up-regulation of IFN--inducible MHC class II, we sought to
consider the effect of MCMV infection on non-IFN--induced MHC class
II molecules in macrophages. Macrophages are believed to be among the
earliest cells infected by MCMV. We report a novel mechanism by which
MCMV causes a decrease in the expression of MHC class II in
macrophages, by inducing IL-10 production in the infected cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Five- to six-week-old female C57BL/6J mice were obtained from The Scripps Research Institute Animal Resources Facility (La Jolla, CA). IL-10-deficient animals (12) were obtained from Drs. B. Balasa and N. Sarvetnick, Department of Immunology, The Scripps Research Institute.
Cells
The mouse macrophage cell line IC-21 (13), the mouse mammary epithelial tumor cell line C127I (14), and the murine fibroblast cell line NIH 3T3 (ATCC CRL1658) were obtained from the American Type Culture Collection (Manassas, VA). C127I cells were maintained in DMEM supplemented with 10% FCS, 10 U/ml penicillin G, 10 µg/ml streptomycin, and 2 mM glutamine. NIH 3T3 fibroblasts were cultured in DMEM as above, except with 10% FBS. IC-21 cells were grown in RPMI medium supplemented in the same way, with the addition of 5 x 10-5 M ß-ME.
Primary macrophages were elicited from peritoneal exudate cells (PECS) following i.p. injection of 1 ml thioglycolate (Becton Dickinson, Cockeysville, MD) into either C57BL/6 or IL-10-deficient mice. PECS were removed by peritoneal lavage. Cells were plated out at 1–5 x 106/ml, and incubated for 24–48 h at 37°C, 5% CO2, after which nonadherent cells were washed away with PBS. Before staining with appropriate Abs, macrophages were removed from the plates by gentle scraping, and washed in PBS.
Virus stocks and infections
Viral stocks are routinely tested for mycoplasma, and all stocks used in this study were mycoplasma free. Salivary gland-passaged stocks of MCMV (Smith ATCC VR-1399) were used to infect C57BL/6 or IL-10-deficient mice by i.p. injection. A total of 5 x 103 PFU of MCMV was injected in 200 µl of DMEM. Control animals were age and sex matched, and were mock infected with 200 µl of DMEM only. Animals were sacrificed 24 h postinfection, and the spleens were removed. Mononuclear cells were harvested by preparation of a single cell suspension, and removal of erythrocytes by hypotonic lysis.
Stocks of tissue-propagated MCMV viruses were prepared in NIH 3T3 cells, and titers were determined by standard plaque assay on NIH 3T3 cells. For in vitro assays, both the Smith strain of MCMV and the rMCMV RM461 (strain K181) were used. The RM461 rMCMV carries the LacZ gene, and detection of infected cells can be made by staining for ß-galactosidase activity. RM461 MCMV was originally obtained from E. S. Mocarski (Stanford University, Stanford, CA). Cells were infected with MCMV at a multiplicity of infection (moi) of 10. Adsorption was for 1 h at 37°C, 5% CO2, with gentle rocking of cells every 15 min. Cells were then washed in PBS before fresh medium was added.
Cells infected with MCMV RM461 were detected by staining for expression
of ß-galactosidase. Cells were fixed for 5 min at room temperature in
0.5% gluteraldehyde, and then stained for 24 h at 37°C in
staining solution (1 M MgCl2, 5 M NaCl, 0.5 M HEPES, pH
7.4, 30 mM potassium ferrocyanide, 30 mM potassium ferricyanide, 2%
X-Gal (5-bromo-4-chloro-3-indolyl ß-D-galactoside) in
N,N-dimethylformamide). For viral growth kinetic
studies (Fig. 1
), cells were infected at moi = 0.1. Infectious
MCMV from cellular extracts or present in the culture supernatant was
measured by standard plaque assay at day 1–8 postinfection.
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Abs and flow cytometry
In all flow cytometry experiments, FcR binding of Abs was
blocked by incubation of cells with blocking buffer (PBS, 5% v/v
heat-inactivated rabbit serum, 1% w/v sodium azide, 30 min at 4°C),
before staining. Expression of MHC class II on IC-21 cells and primary
macrophages was detected with BP107.2.2 (ATCC TIB154), followed by goat
anti-mouse IgG and FITC-conjugated anti-goat IgG (Sigma, St.
Louis, MO). Detection of MHC class II on splenic macrophages and on
C127I cells was made with FITC-conjugated 14-4-4S (for C127I cells) or
25-9-17 (for splenic macrophages) (both Abs from PharMingen, San Diego,
CA). The macrophage marker F4/80 was detected with anti-F4/80 (ATCC
HB198) and amplified with biotinylated anti-rat IgG and
streptavidin-R613 (PharMingen). CD11c (N418) was stained using
PE-conjugated Ab (PharMingen). Analysis of cells was made by flow
cytometry with a FACS Calibur instrument (Becton Dickinson, Mountain
View, CA). A total of 50,000 events were collected per sample.
Analysis of MHC class II expression on ex vivo splenic cells was made in the following way: C57BL/6 and IL-10-deficient mice were injected i.p. with MCMV (5 x 103 PFU). Twenty-four hours postinoculation, animals were euthanized and spleens were removed. Mononuclear cells were stained for F4/80 or CD11c expression, and sorted into single populations by flow cytometry (FACStar; Becton Dickinson, Mountain View, CA), before staining for MHC class II.
For detection of intracellular cytokine expression, primary macrophages
(PECS) were mock infected (with DMEM only) or infected with MCMV at moi
of 10 for 24 h. Subsequently, cells were incubated with 10 µg/ml
Brefeldin A (Sigma) for 4 h at 37°C, as described (15). Cells
were then washed with PBS, permeabilized using a Fix & Perm kit (Caltag
Laboratories, Burlingame, CA), and stained using anti-cytokine
reagents. The Abs used were PE-conjugated anti-IL-10 (JES5-16E3),
anti-IL-4 (11B11), anti-IFN- (XMG1.2), and a PE-conjugated
isotype control (rat IgG1). All Abs were purchased from PharMingen.
Control samples that were not permeabilized were also included.
Neutralization of MHC class II down-regulation with Abs
Macrophages (IC-21) were infected with MCMV, in vitro, as described. Conditioned supernatant from infected or noninfected controls was incubated with an anti-IL-10 Ab (JES5.2A5), or an isotype-matched control (YCATE55) for 30 min at 37°C. Treated supernatants were added to noninfected cells, and the cells were then incubated for 24 h, before staining for MHC class II expression. Control samples of noninfected, nontreated cells and directly infected cells were included.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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During the acute phase of MCMV infection, macrophages readily aid
the spread of the virus to secondary sites of infection (16), and are
one of the cellular sites of latency for MCMV (17). Using a macrophage
cell line, IC-21, which is susceptible to MCMV infection (Ref. 18 and
Fig. 1
A), we examined how MCMV
infection affected the surface expression of constitutively expressed
MHC class II proteins. IC-21 cells are derived from C57BL/6 and express
I-Ab MHC class II molecules on their surface. Following
infection of IC-21 cells with MCMV in vitro, we observed that the
expression of constitutive MHC class II was dramatically decreased
(Fig. 2A). The mean
fluorescence intensity (MFI) of cells expressing MHC class II decreased
from 446 to 173, a reduction of 61%, 24 h after infection (Fig. 2A). To investigate whether MCMV infection of primary
macrophages could also cause decreased expression of MHC class II
proteins, macrophages were isolated from C57BL/6 mice and infected with
MCMV. These cells are also susceptible to MCMV infection (Fig. 1B). Analysis of the MHC class II expression in these
macrophages 24 h after infection revealed that class II expression
is also significantly reduced in primary macrophages in comparison with
the noninfected controls (Fig. 2B). The MFI of MHC class II
on macrophages decreased from 1985 to 834, a reduction by 58%, 24
h following MCMV infection (Fig. 2B). A decrease in MHC
class II expression was not observed in cells that were treated with
UV-inactivated virus (Fig. 2C). Thus, live, infectious virus
is necessary for this process, suggesting a requirement for viral gene
expression.
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D). This result suggests that down-regulation of MHC class
II is specific, and not a result of global down-regulation of
activation markers. We next sought to examine whether this
down-regulation occurred only in macrophages. For this purpose, we
infected an epithelial-derived tumor cell line, C127I, which
constitutively expresses MHC class II (Fig. 2E), and is
fully permissive for MCMV (Fig. 1C). Production of
infectious virus in C127I cells was comparable with that obtained in
NIH 3T3 cells (Fig. 1D), which are fibroblasts that fully
support MCMV replication. MCMV infection of C127I did not result in
decreased expression of MHC class II (Fig. 2E). Assessment
of MHC class II expression on C127I cells at time points from 24–96 h
following infection revealed that MHC class II was not affected from
24–48 h, and slightly increased at 72–96 h (data not shown). Thus,
the effect was apparent in macrophages, but did not extend to
epithelial-derived cells 24 h after infection. These experiments
provide evidence that MHC class II protein expression is specifically
and selectively decreased 24 h following MCMV infection of
macrophages. Reduction of MHC class II expression in uninfected cells by culture supernatant from MCMV-infected macrophages
In the experiments described above, infections were conducted
under conditions that limited the proportion of cells infected in the
culture to approximately 20%. Since the reduction in expression of MHC
class II on the surface of MCMV-infected macrophages affected almost
all of the cells, we reasoned that secretion of a soluble factor such
as a cytokine from the infected cells could be responsible for the
effect. To test this hypothesis, culture supernatants from IC-21 cells
infected with MCMV (for 24 h) were transferred to fresh,
noninfected IC-21 cells and to control, epithelial-derived tumor cells
(C127I). As expected, direct infection of IC-21 cells with MCMV caused
a reduction in the level of MHC class II expression, with a decrease in
staining from MFI 145 to MFI 78 (Fig. 3B). Significantly,
macrophages incubated with the conditioned supernatant for 24 h
also showed a decrease in the level of MHC class II detection (MFI 145
to 87) (Fig. 3, A and C). By contrast, reduction
in class II expression was not observed in the epithelial tumor cell
line, C127I (Fig. 3D). It was important to exclude the
possibility that this effect was due to the presence of live virus in
the culture supernatant. Supernatants from MCMV-infected IC-21 cells
were treated with UV light, to inactivate any live virus present, and
then incubated with noninfected IC-21 cells. Live virus was not
detected in the UV-treated supernatant (see Materials and
Methods for details). MHC class II expression was still decreased
in noninfected IC-21 cells incubated with these test supernatants (data
not shown), indicating that transfer of any contaminating live virus to
noninfected cells is unlikely to be responsible for the effect. These
data strongly support the notion that a soluble factor, most likely a
cytokine, present in the supernatant from MCMV-infected macrophages, is
responsible for the reduction of MHC class II expression on the surface
of the cells.
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Several cytokines reportedly cause down-regulation of MHC class II
proteins on APC, including IL-10 (19, 20). Accordingly, we next
examined the production of IL-4, IL-10, and IFN- by MCMV-infected
primary macrophages from C57BL/6 mice. For these experiments, detection
of intracellular cytokine expression was measured by flow cytometry
using specific Abs. We found that IL-10 was expressed in MCMV-infected
macrophages 24 h following infection, but not in the noninfected
controls (Fig. 4, A and
D). Approximately 20–30% of the cells examined stained
positive for IL-10. IL-4, which is not normally produced by
macrophages, was included as a negative control. Staining of IL-4 was
not detected in macrophages (Fig. 4, B and E).
While it is accepted that the majority of IFN- is made by NK and T
cells, IFN- may also be produced by macrophages. It has been
reported that low levels of IFN- are constitutively expressed by
resting macrophages and that it is up-regulated in an autocrine manner,
following activation of the cells (21). IFN- causes the
up-regulation of MHC class II expression at later stages in MCMV
infection. IFN- was not detected at this early stage (24 h) in the
infection (Fig. 4F). These data implicate IL-10 as a
candidate cytokine involved in causing down-regulation of MHC class II
in MCMV-infected macrophages.
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To test that IL-10 production by MCMV-infected macrophages is, at
least in part, responsible for the down-regulation of MHC class II on
the surface of infected cells, we used neutralizing Abs against IL-10.
Conditioned (MCMV-infected) culture supernatant removed 24 h
postinfection from primary macrophages was incubated with either
anti-IL-10 Ab (0.1–20 µg/ml) or an isotype-matched control, and
then used to treat noninfected cells (Fig. 5A). The inhibition of MHC
class II expression by MCMV-conditioned supernatants was reduced in a
dose-dependent manner by the anti-IL-10 neutralizing Ab (Fig. 5A). An isotype control Ab did not neutralize the effect of
IL-10 (Fig. 5B). The results of these experiments identify
IL-10 as an essential mediator of MCMV down-regulation of MHC class II
in macrophages.
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To establish a direct role of IL-10 in the reduction of
constitutively expressed MHC class II in MCMV-infected macrophages, we
next studied cells taken from IL-10-deficient (knockout) mice (12). As
expected, when primary macrophages from C57BL/6 mice were infected in
vitro, a reduction in MHC class II expression of 30% (from MFI 2850 to
2000) was observed (Fig. 6A).
In marked contrast, surface expression of MHC class II in MCMV-infected
primary macrophages taken from IL-10-deficient mice at 24 h
postinfection was unchanged (Fig. 6B). To determine whether
there was a difference in susceptibility of the cells to MCMV
infection, we took advantage of a mutant version of MCMV strain RM461,
which carries a LacZ gene. Cells were stained for expression
of ß-galactosidase activity as a measure of cellular infection.
Similar levels of infection were observed between cells taken from
C57BL/6 mice (12.5 ± 3.1% cells infected) and cells from
IL-10-deficient mice (19.8 ± 3.9% cells infected) at 24 h
(data not shown).
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, C and D).
These data strongly suggest that in primary macrophages infected with
MCMV, IL-10 plays an essential role in the decreased expression of
uninduced MHC class II 24 h following infection. Reduction of MHC class II in splenic macrophages and dendritic cells following acute MCMV infection
We next evaluated the expression of MHC class II on splenic cells
following acute MCMV infection. For this purpose, we compared
populations of macrophages (F4/80+) and dendritic cells
(CD11c+) taken from C57BL/6 and IL-10-deficient mice,
24 h following infection. There was a clear decrease in MHC class
II expression on both F4/80+ and CD11c+ cells
from C57BL/6. The resting macrophages express very low levels of class
II (MFI 8), but this goes down to MFI 5 in the infected cells (Fig. 7A). The resting level of
class II on the dendritic cells (CD11c+) was much higher
(MFI >104), and was dramatically decreased in cells from
infected mice (Fig. 7B). Cells from the IL-10-deficient mice
showed significant increases in the level of expression of MHC class II
following MCMV infection, in both macrophage (F4/80+) and
dendritic cell (CD11c+) populations (Figs. 7C
and 5D). The macrophages showed an increase in staining of
MHC class II from MFI 14 to more than 103 (Fig. 7C). The MCMV-infected dendritic cells also increased class
II expression (Fig. 7D). These data suggest that IL-10 plays
a pivotal role in the reduction of MHC class II expression in splenic
macrophages and dendritic cell populations, in the early stages of
infection with MCMV. In contrast, in the absence of IL-10, expression
of class II is strongly increased in these cellular populations.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the work presented in this study, we have shown that MCMV infection
of macrophages results in a decrease in MHC class II on the surface of
the cells, very early in the inflammatory response. This effect is
apparent (in vivo and in vitro) within 24 h of infection prior to
stimulation by IFN- and is mediated, at least in part, by induction
of IL-10 production. IL-10 causes a reduction in the level of
expression of MHC class II proteins by interfering with exocytosis and
recycling of the proteins (19, 20). This delineates a mechanism by
which MCMV infection immediately begins to interfere with the host
immune system, and would likely impair the ability of the macrophages
to present Ag to CD4 T cells by decreasing MHC class II expression. In
addition, IL-10 has other immunosuppressive effects, including
inhibition of production of inflammatory cytokines. This early effect
illustrates again the remarkable variety of CMV strategies for
dampening the immune response. The effect differs from previously
reported mechanisms by which MCMV impairs MHC class II expression in
macrophages, which involve induction of IFN-ß (28), and impairment of
IFN- induction of MHC class II (10, 11). Since CMV is known to have
several strategies to interfere with the host cell expression of MHC
class I, it is not surprising that the virus also has several
mechanisms to inhibit MHC class II expression. It is also worthwhile to
note that IL-10 has been reported to cause down-regulation of MHC class
I in studies with tumor cells (29, 30) and B cell lines (29).
The role of cytokines in viral infections is complex, and has not yet
been fully characterized. There have been several studies to evaluate
cytokine production in MCMV infection. It is known that NK cells
contribute to early defense against MCMV. In acute MCMV infection of
C57BL/6 mice, it was found that IFN- and TNF were produced 48 h
postinfection (31), and that NK cells were solely responsible for
IFN- production in this situation. It has also been shown that the
IFN- production by NK cells in MCMV infection is dependent on IL-12
induction (32). Additionally, IFN-/ß produced in MCMV infection
could mediate IFN-/ß-dependent NK cell cytotoxicity (33). In the
same study, it was shown that TNF, IL-12, and IFN- were present in
the serum of MCMV-infected C57BL/6 mice, 2 to 3 days postinfection
(33). It has been demonstrated that in MCMV infection, IFN-ß can
also act as a regulator of IL-12 and IFN- (34). Recent reports have
also shown that MCMV-mediated hepatitis may be attributable to TNF
production (35), independent of NK and T cell contribution, and that
peritoneal cells produce IL-1 and TNF- in MCMV infection (36).
In data presented in this work, we have shown that MCMV-infected
macrophages taken from IL-10-deficient mice did not exhibit a reduction
in the expression of MHC class II following MCMV infection. Indeed,
macrophages from IL-10-deficient mice showed increased expression of
class II. This may be a consequence of the elevated serum levels of
IFN- that are known to be present in IL-10-deficient mice (12). The
level of IFN- would be expected to rise further following MCMV
infection, leading to an increase in the level of MHC class II on
affected cells. In contrast, macrophages taken from IL-10-sufficient
C57BL/6 mice showed a reduction in the level of constitutively
expressed MHC class II following infection. These data strongly suggest
a role for IL-10 in causing the reduction in MHC class II levels in
MCMV infection of macrophages.
The induction of IL-10 very early in MCMV infection would immediately
help the virus to avoid detection by the host adaptive immune system,
by reducing the capacity of the infected macrophages to present
antigenic peptides to CD4 cells. It has already been reported that at
48 h following MCMV infection, IFN-/ß plays an important role
in causing reduction of MHC class II proteins in bone marrow-derived
macrophages (28). In MCMV-infected macrophages, the virus can also
interfere with MHC class II expression by affecting the IFN-
receptor via a mechanism that is independent of IFN-/ß involvement
(10). Taken together, this suggests that the sequential activation of
IL-10 and IFN-/ß-dependent and IFN-/ß-independent response
pathways is likely to be important in the ability of MCMV to impair Ag
presentation by infected macrophages in the very early stages of
infection.
Another Herpesvirus, EBV, encodes a viral homologue of IL-10, which shares many of the cellular cytokine’s biological activities (37). However, there is no indication of any effect on MHC class II expression on B cells infected with EBV (37). IL-10 has also been shown to be important in infections with other intracellular pathogens, including infection of macrophages with Listeria monocytogenes and Mycobacterium bovis (38). It has also been reported that infection of human alveolar macrophages in culture by respiratory syncytial virus induced secretion of IL-10 by the infected cells (39). It thus seems likely that pathogen manipulation of the IL-10-mediated pathways in infections may be a more widespread phenomenon.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Drs. Nicholas R. J. Gascoigne or Peter Ghazal, Departments of Immunology and Molecular Biology, Division of Virology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. E-mail address:
3 Abbreviations used in this paper: HCMV, human CMV; MCMV, murine CMV; MFI, mean fluorescence intensity; moi, multiplicity of infection; PEC, peritoneal exudate cell.
Received for publication November 10, 1998. Accepted for publication March 10, 1999.
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