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Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4256-4262
Interleukin-10 Abrogates the Inhibition of Epstein-Barr
Virus-Induced B-Cell Transformation by Memory T-Cell Responses
By
M.T. Bejarano and
M.G. Masucci
From the Microbiology and Tumor Biology Center, Karolinska
Institutet, Stockholm, Sweden.
 |
ABSTRACT |
In vitro infection of human B lymphocytes by Epstein-Barr virus
(EBV) results in their growth transformation and establishment of
immortalized lymphoblastoid cell lines. The virus was found to encode a
homologue of the pleiotropic cytokine interleukin-10 (IL-10), which has
wide-ranging effects on the immune system. We investigated the effect
of human IL-10 (hIL-10) and viral IL-10 (vIL-10) on EBV-specific
immunological memory, as assessed by the inhibition of EBV-induced
B-cell transformation by the autologous T cells. We found that IL-10
abrogates the inhibitory capacity of T cells. This IL-10 effect is
mediated through suppression of T-cell activation-induced IL-2 and
interferon- production and through a direct enhancement of
EBV-infected B-cell growth.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
INTERLEUKIN-10 (IL-10) is an
18-kD glycoprotein produced by activated T cells,
monocytes, B cells, and thymocytes. Analysis of the IL-10 coding
sequence showed a high degree of homology to the Epstein-Barr virus
(EBV) open reading frame (ORF) BCRF1.1,2 The mature product
of this ORF was shown to share many of the functional properties to its
cellular counterpart and hence it was termed viral IL-10 (vIL-10).
IL-10 affects the functions of many cell types and has wide-ranging
effects on human B cells. It acts as a costimulatory factor for
activated B cells and also as a B-cell differentiation factor that
promotes secretion of IgA, IgM, and IgG.3 A pleiotropic
effect of IL-10 on apoptosis has also been described. The cytokine
induces apoptosis of chronic lymphocytic leukemia cells and B cells
stimulated with Staphylococcus aureus Cowan strain
(SAC),4 whereas it rescues germinal center B
cells,5 suggesting that the effect of IL-10 depends on the state of B-cellular activation.
IL-10 regulates the growth and differentiation of T cells. It inhibits
antigen-specific activation and proliferation of human T cells and
T-cell clones,6,7 as well as the proliferation, generation
of cytotoxic activity, and cytokine production in mixed lymphocyte
reactions.8 These effects are partially mediated through
inhibition of the function of antigen-presenting cells,9,10 partly through interference of T-cell activation that results in
inhibition of IL-2 production.11-12 Moreover, recent
studies indicate that IL-10 induces a long-lasting antigen
unresponsiveness against alloantigens13 and drives the
generation of T cells with suppressor activity.14
EBV establishes a latent infection in human B cells both in vivo and in
vitro. The virus is associated with several B-cell tumors including
Burkitt's lymphoma (BL), immunoblastic lymphomas in immunosuppressed
individuals, and about 50% of the cases of Hodgkin's disease
(HD).15 Some, but not all, BL lines, acquired immunodeficiency syndrome (AIDS)-associated lymphomas and HD specimens have been shown to produce IL-10.16-19 In addition, the
development of EBV-carrying lymphomas in severe combined
immunodeficiency (SCID)-hu mice involves abundant production of
hIL-10,20 suggesting that IL-10 may play a role in
lymphomagenesis.
In EBV seropositive individuals, the EBV-specific memory response is
manifested in vitro as the ability of T cells to inhibit the growth of
EBV-infected B lymphocytes, a phenomenon designed as outgrowth
inhibition (OI).21 Given that IL-10 has profound effects on
cells involved in the immune response, the aim of this work was to
determine the influence of IL-10 on the immunity relevant to EBV
infection. Our results show that IL-10 abrogates the growth inhibitory
capacity of the T cells and also affects the growth of EBV-infected B
cells.
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MATERIALS AND METHODS |
Medium and reagents.
Cultures were maintained in RPMI 1640 (GIBCO-BRL, Gaithersburg,
MD) supplemented with 10% fetal calf serum (FCS), 100 U/mL penicillin and 2 mmol/L L-glutamine, referred to as complete
medium. Recombinant hIL-10 (specific activity 107 U/mg) and
vIL-10 (specific activity 5 × 106 U/mg) were kindly
provided by DNAX Research Institute, Palo Alto, CA. Unless otherwise
indicated, the concentration of IL-10 used was 100 U/mL. Recombinant
human IL-2 and interferon- (IFN-) were generously provided by
Hoffman LaRoche (Nutley, NJ) and were used at a final concentration of
20 U/mL and 100 U/mL, respectively.
Outgrowth inhibition assay.
OI assays were performed as described earlier.22 Briefly,
Ficoll isopaque-separated peripheral blood lymphocytes (PBLs) from EBV
seropositive donors (EBV S+) were depleted of macrophages
by plastic adherence and EBV infected by exposure to supernatants of
the virus producer B958 cell line for 2 hours at 37°C. The infected
PBLs were seeded by doubling dilutions ranging from 8 × 105 to 1.5 × 104 cells/well in
flat-bottomed microtiter plates in a final volume of 200 µL. Five
replicates of each dilution were performed in the absence and in the
presence of 100 U/mL of IL-10. In some experiments IL-10 was added at
day 4 after infection. The cultures were incubated at 37°C/5%
CO2 and fed once per week by replacing half of the medium
with fresh complete media with or without IL-10. Four to 5 weeks later,
the growth was evaluated visually22 and by
3H-thymidine (TdR) incorporation. The strength of the OI is
expressed as OI index that reflects the minimum number of cells/well
required for 50% reduction of B-cell growth. This value was calculated by plotting the mean % inhibition versus the log of the cell
concentration/well. A regression line was obtained from which the
minimum number of cells/well required for 50% inhibition was
calculated. Wells were pulsed with 1 µCi of 3H-TdR
(Amersham, Amersham, UK) 12 hours before harvesting onto a
fiberglass filter and the 3H-TdR incorporation was
determined by liquid scintillation counting.
Isolation of CD4+ and CD8+
enriched populations.
CD4+ and CD8+ populations were obtained by
negative selection. Aliquots of PBLs depleted of macrophages by plastic
adherence were incubated with saturating concentrations of anti-CD4 or
anti-CD8 monoclonal antibody (MoAb) for 30 minutes at 4°C. Cells
were washed twice with Hanks' Balanced Salt Solution (HBSS) and
subsequently rosetted with magnetic beads coated with sheep antimouse
IgG (Dynabeads M-450 sheep antimouse IgG, Dynal AS, Oslo, Norway) at a
bead to cell ratio of 20:1. The mixture was incubated for 30 minutes at 4°C with gentle shaking before removal of rosetted cells with a
magnetic particle concentrator according to the manufacturer's recommendations. The resulting cell preparations contained less than
5% of the depleted population as assessed by staining with fluorescein
isothiocyanate (FITC) goat anti-mouse Ig.
Analysis of IL-10 effect on EBV-induced B-cell proliferation.
Purified B cells were obtained from PBL depleted of adherent cells by
plastic adherence and iron phagocytosis and further fractionated into
T- and B-cell enriched populations by nylon wool passage.23
B cells were collected from the nylon adherent fraction and further
purified by negative selection with anti-CD3 MoAb-coated magnetic beads
(Dynabeads M-450 anti CD3; Dynal) according to manufacturer's
recommendations. The recovered cells were exposed to B958 cell
supernatants for 2 hours at 37°C, washed, and resuspended in
complete media. The infected cells were seeded in triplicates at a
concentration of 5 × 104/well in 200 µL vol in
96-flat bottomed microplates in the presence of various concentrations
of IL-10. Seven days later, B-cell proliferation was assessed by
3H-TdR incorporation during the last 8 hours of the
incubation period.
Lymphokine determination.
Supernatants collected at days 1, 2, and 3 after EBV infection were
assayed as duplicates for their content of IL-2, IL-4, IL-5, IL-6,
IL-10, IFN-, granulocyte-macrophage colony-stimulating factor
(GM-CSF), and tumor necrosis factor- (TNF-) by
lymphokine-specific enzyme-linked immunosorbent assays (ELISA) as
described previously.8 The sensitivity of the various ELISA
were: 10 pg/mL for IL-2; 40 pg/mL for IL-4, IL-5, and IL-10; 100 pg/mL
for GM-CSF, IL-6, and IFN-; and 20 pg/mL for TNF-.
| |
RESULTS |
IL-10 prevents the inhibition of EBV-induced B-cell transformation by
autologous T cells.
The effects of exogenous IL-10 (human and viral) on the
T-cell-mediated inhibition of EBV-induced transformation of B cells was analyzed in OI assays that are known to reflect an EBV-specific memory response. The strength of the OI is expressed in terms of the
initial number of cells/well required for 50% reduction of
B-lymphocyte growth. The reported mean value for healthy seropositive individuals is 1.9 × 105 cells/well with a range
between 0.3 to 6.3 × 105.24 One
seronegative and 11 seropositive donors were tested. When IL-10 was
added to the cultures immediately after EBV infection, it reduced the
growth inhibitory capacity in all instances, independent of the initial
strength of the inhibition. The same effect was observed with both
hIL-10 and vIL-10 (donors 1 to 8 and 9 to 11, respectively). When
tested in parallel, human- and viral-IL-10 displayed comparable
inhibitory capacity (donors 9 to 11). The outcome of the assay was not
affected in one case where the donor was EBV seronegative and thus did
not exhibit OI response (Fig 1).
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| Fig 1.
Effect of IL-10 on the OI. EBV-infected PBL from 11 seropositive and one seronegative (EBV S ) donors were
seeded at various cell concentrations in flat-bottomed microtiter
plates in medium control or medium containing 100 U/mL of IL-10. Four
to 5 weeks later the transformation was visually scored. The results
are expressed as OI index representing the minimum number of cells/well
required to achieve 50% inhibition of EBV-induced transformation.
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IL-10 potentiates the growth of EBV-transformed cells.
IL-10 is known to be involved in the proliferation and autonomous
growth of EBV-transformed B cells.25-27 Therefore, we
tested the effect of exogenous IL-10 on the EBV-induced B-cell
transformation. To this end, purified B cells were exposed to the virus
and cultured in the presence of various concentrations of hIL-10 and
vIL-10. Seven days later, the proliferation was assessed by
3H-TdR incorporation. IL-10 increased the proliferation of
B cells in a dose-dependent fashion. At high doses, ie, 400 U/mL, the enhancing effect declined (Fig 2). A
potentiating effect of IL-10 on B-cell growth/transformation was also
observed in the OI assays when the number of PBL seeded per well was
equal or below 2.5 × 104. Under these conditions, the
number of EBV-specific T-cell precursors is too low to prevent
EBV-induced transformation; in addition, the proportion of B cells that
undergo transformation is also low, and/or a feeder effect is
required to sustain growth. In the presence of IL-10, there was a
higher frequency of wells with transformation compared with control
cultures. This effect was reflected in the 3H-TdR
incorporation values (Table 1). In
accordance with previous reports,25,27 B-cell
transformation was strongly inhibited by the addition of anti-IL-10
antibodies (data not shown).
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| Fig 2.
Effect of IL-10 on the proliferation of EBV-infected B
lymphocytes. Purified B cells were infected with EBV and cultured in
flat-bottomed microtiter plates in the presence of different
concentrations of IL-10. Seven days later the proliferation was
evaluated by 3H-TdR incorporation. The results expressed
mean cpm of triplicate samples. The standard deviation (SD) was lower
than 10%. One representative experiment of three is shown.
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Kinetics of the IL-10 effect.
We have shown previously that the first 3 days after viral infection
are crucial for the outcome of the OI. When T cells or cytokines, such
as IFN- are added after this period, their inhibitory effects are no
longer observed or are substantially reduced.24,28 Therefore, we tested whether IL-10 can exert its effect if added 72 hours after infection. Experiments were performed in which hIL-10 was
added immediately after infection or at day 4. As shown in
Fig 3, IL-10 was effective in abrogating
the OI response only if present from the outset of the culture period,
when added at day 4, the OI values were as those of the control
cultures. The kinetics of the IL-10 effect was the same independently
of the initial strength of the OI response.
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| Fig 3.
Kinetics of the IL-10 effect on the OI. OI assays were
performed as described in Materials and Methods. IL-10 was added either
from the outset of the culture period or on day 4. Four to 5 weeks
later the transformation was visually scored. The results are expressed
as OI index representing the minimum number of cells/well required to
achieve 50% inhibition of EBV-induced transformation.
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IL-10 inhibits cytokine production.
IL-10 appears to act predominantly as an immunosuppressive agent,
inhibiting the proliferation of T cells and the production of cytokines
in response to allo- and soluble antigens.8,9,11 Thus, we
set out to test the effect of IL-10 on the production of IL-2, IL-3,
IL-4, IL-5, IL-6, IL-13, GM-CSF, IFN-, and TNF- in the
EBV-infected cultures. A single determination was performed at day 3 in
most experiments. However, given the fact that various cytokines have
different kinetics of production, supernatants from EBV-infected PBLs
cultured with or without IL-10 were harvested at days 1, 2, and 3 in
two experiments. Five different experiments are shown in
Table 2 where results from the experiments
1, 2, and 3 correspond to the OI assays of donors 1, 3, and 6 depicted in Fig 1. We could not detect production of IL-4, IL-5, and GM-CSF (not
shown), while significant levels of IL-2, IL-6, IL-10, TNF-, and
IFN- were found in the supernatants. Addition of IL-10 resulted in
substantial reduction of IL-2 and TNF- production. The production of
IFN- and IL-6 was affected to a lesser extent, although the levels
were significantly decreased compared with the control cultures
(P values < .05) (Table 2).
The inhibitory effect of IL-10 can be neutralized by exogenous IL-2.
The reduction of IL-2 and IFN- production are well-documented
effects of IL-10, which are responsible for the inhibition of T-cell
responses.8,11,12 Originally, IL-10 was described as a
cytokine that inhibits IFN- production by peripheral blood mononuclear cell (PBMC) after activation by phytohemagglutinin (PHA) or anti-CD3 MoAb.29 IL-10 was shown to
act directly on human T cells triggering a signalling pathway that
specifically inhibits IL-2 synthesis.11,12 Hence, we
investigated whether exogenously added IL-2 or IFN- could overcome
the inhibitory effects of IL-10 in the OI. To this end, IL-2 or IFN-
were added to the IL-10 containing cultures from day 0. Addition of
IL-2 neutralized the effect of IL-10; the inhibition of transformation in the IL-2 supplemented cultures was even stronger than in the control
cultures. In contrast, IFN- could only partially overcome the
inhibitory effect (Fig 4).
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| Fig 4.
The OI is reconstituted by exogenous IL-2, but not by
IFN-. Four replicate plates were performed for OI as follows: (1)
medium control, (2) medium containing 100 U/mL of IL-10, (3) medium
containing 100 U/mL of IL-10 and 10 U/mL of IL-2, (4) medium containing
100 U/mL of IL-10 and IFN-. Four to 5 weeks later the transformation
was visually scored. The results are expressed as OI index representing
the minimum number of cells/well required to achieve 50% inhibition of
EBV-induced transformation. One representative experiment of three is
shown.
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The inhibitory effect of IL-10 is potentiated in the presence of
CD4+ T cells.
We have demonstrated previously that the OI is the end result of a
combination of inhibitory activities mediated by soluble factors as
well as cytotoxic cell responses exerted by T cells and natural killer
(NK) cells.22,24,28 Studies involving the separation of T
cells into CD4+ or CD8+ populations showed that
the CD8+ cell compartment is the main effector in the
OI.30 To dissect the effect of IL-10 on CD4+ or
CD8+ T cells, OI assays were performed with PBLs enriched
in CD4+ or CD8+ cells by negative selection.
Using these fractionated populations, we confirmed that the
CD8+, but not the CD4+ cells, play a major role
in the OI. In the absence of CD8+ cells, 50% inhibition
was not observed even at the highest cell number seeded, ie, 8 × 105/well. Conversely, the OI capacity of the
CD8+-enriched population was stronger than that of the
total population (twofold reduction in the number of cells/well
required for 50% inhibition). The IL-10 inhibitory effect was more
evident in the total population. The inhibitory effect of the
CD8+-enriched population was reduced by threefold compared
with sevenfold reduction in the total population
(Fig 5).
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| Fig 5.
Effect of IL-10 on the outgrowth inhibitory capacity of
CD4+ and CD8+ populations.
CD4+- and CD8+-enriched PBL populations
were obtained by negative depletion of CD8+ and
CD4+ cells, respectively, and thereafter infected with
EBV. OI assays were performed as described in medium alone or medium
containing 100 U/mL of IL-10. Four to 5 weeks later the transformation
was visually scored. The results are expressed as OI index representing
the minimum number of cells/well required to achieve 50% inhibition of
EBV-induced transformation.
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DISCUSSION |
In this study, we show that IL-10 abrogates the inhibitory activity
that T cells from EBV seropositive individuals have on the EBV-induced
transformation of autologous B cells. This reflects a combination of
enhancing effects on EBV-induced B-cell proliferation on one hand and
inhibitory effects on T-cell reactivation on the other.
EBV appears to have acquired a number of unique functions that enhance
its ability to colonize the B-cell system and to persist as a latent
infection within the B-cell pool despite the continuous presence of
cytotoxic T lymphocyte (CTL) surveillance. IL-10
contributes to these strategies in several ways. IL-10 promotes the
efficiency of virus-induced transformation through its capacity to
enhance the proliferation and survival of the infected B cells. Viral IL-10 is expressed during the late phase of the lytic cycle, but has
also been detected by reverse transcriptase-polymerase chain reaction
(RT-PCR) within 6 hours after viral infection.31 This early
expression of the viral product is followed, 20 to 30 hours later, by
the virally induced expression of hIL-10.25,31 Expression of the EBV latent membrane antigen (LMP-1) upregulates hIL-10 production in transfected sublines of EBV- Burkitt's
lymphomas.32 Studies involving vIL-10 showed an enhancing effect on EBV-induced transformation that was due to an increase in the
viability of the infected B cells.26 Addition of exogenous hIL-10 potentiates the proliferation of infected B cells,25 and hIL-10 was shown to act as an autocrine factor promoting the growth
of spontaneously derived lymphoblastoid cell lines from patients with
EBV-associated lymphoproliferative disorders.27 Therefore,
vIL-10 may exert these growth enhancing effects in the earlier phases
after EBV infection, before the induction of the cellular IL-10, which
is known to peak 3 to 4 days after infection.31 In our
hands, this promoting effect was reflected in the levels of
proliferation in the transformation assays as measured by
3H-TdR incorporation and also in the OI assays. In the
latter, when the number of cells/well seeded was low (below or equal to 2.5 × 104 total PBL with a proportion of B cells
between 10% to 15%), the incidence of transformation was enhanced in
the presence of IL-10. These findings are in line with previous
reports25,31 and our own observation that B-cell
transformation is affected in the presence of anti-IL-10 antibodies.
Relevant to the B-cell growth promoting effect of IL-10 is also its
capacity to inhibit the production of IFN-, which is important in
the early control of EBV infection/transformation. IFN- inhibits
EBV-induced B-cell proliferation only if added during the first 72 hours after viral infection, before the transformed phenotype is
established.33 Notably, while the transforming ability of
viruses in which the vIL-10 gene was deleted was not affected, the
lymphoblastoid cell lines (LCLs) obtained by
transformation with the mutant viruses induced higher levels of IFN-
production by allogeneic PBL than the LCLs established with the
wild-type virus.34
A direct effect of IL-10 on the T-cell-mediated control of B-cell
transformation may involve modulation of CTL recognition. Recently, it
was shown that vIL-10 downregulates the expression of the transporter
associated with antigen presentation-1 (TAP1) in primary B lymphocytes
after EBV infection. As a consequence, vIL-10 causes a general
reduction of surface major histocompatibility complex (MHC) class I
molecules that could affect the presentation of viral antigens to T
cells.35 Similar mechanisms are used by other herpes
viruses.36 An immediate early gene product of Herpes
simplex virus (HSV) inhibits the TAP-dependent peptide translocation.37,38 Various early gene products of human
cytomegalovirus (HCMV) prevent antigen presentation in a sequential
multistep process by modifying the intracellular transport of MHC class I molecules and also by preventing peptide loading within the endoplasmic reticulum.39,40 It is noteworthy
that EBV has evolved a specialized strategy for preventing presentation
of a latency-associated antigen, EBNA-1. Recognition of EBNA-1 by MHC
class I restricted CTLs is inhibited by the presence of a Gly-Ala
repeat domain, which appears to prevent ubiquitin/proteasome-dependent
processing.41 The product of the BZLF2 ORF encodes a type
II membrane glycoprotein expressed during lytic infection that binds
the  chains of MHC class II and thus blocks class II antigen
presentation.42
The present report suggests an additional advantage for the virus in
capturing this cytokine homologue, namely the suppression of specific
T-cell responses manifested as the capacity of T cells to inhibit
EBV-induced B-cell transformation. We have previously shown that
activation of T cells, as well as IFN- production during the early
phases of EBV infection, are crucial in determining the outcome of the
OI. Cyclosporin-A abolished the OI capacity of T cells if present
during the first 3 days after viral infection and exogenously added
IL-2 could neutralize this effect.28 The kinetics of the
IL-10 effect showed the same pattern. In the OI system, the IL-10
effect appears to be explained mainly by abrogation of the IL-2
production. This assumption is substantiated by the fact that addition
of exogenous IL-2 could restore the OI, while IFN- had only a
partial effect. Therefore, the critical consequence of the IL-10 effect
is the inhibition of expansion of the reactivated T cells. We have
described a similar IL-10 effect on the proliferative and cytotoxic
responses to alloantigens.8 In that study, we showed that
the effect of IL-10 is at the level of IL-2 production rather than IL-2
consumption because the inhibitory effect of IL-10 was also evident in
the presence of anti-IL-2R antibodies.
Our results differ from those reported by Stewart and
Rooney43 who showed that transfection of vIL-10 into an
EBV+ BL line, or addition of vIL-10 to PBL cultures
stimulated with autologous or allogeneic LCLs, results in enhanced
generation of allo-specific CTL, EBV-specific CTL, and HLA unrestricted
killing. The discrepancy may have several explanations. In the
experiments of Stewart and Rooney, EBV-specific CTLs were reactivated
by exposure to already transformed B cells. Thus, the enhancing effects
of IL-10 could be partially explained by an activating effect on B-cell
lines. It is noteworthy that in our previous studies on modulation of
alloreactivity, the inhibitory effect of IL-10 on T-cell proliferation
and generation of cytotoxicity was not evident when EBV-transformed
LCLs were used as stimulators.8 In the present study, IL-10
was added from the beginning of the cultures when T cells are exposed
to infected B cells at a very early stage of transformation. It is
likely that the early steps of T-cell activation are influenced by
parameters such as the number and phenotype of the stimulator cells
where expression of costimulatory molecules and/or different
patterns of viral antigens may be critical. Furthermore, it was
recently shown that IL-10 induces antigen-specific unresponsiveness13; whether this is an additional mechanism in the IL-10-mediated inhibition of EBV-specific responses remains to
be determined.
In accordance with a previous study,30 the CD8+
population seems to play a major role in the OI. We have observed that
although the strength of the CD8+-mediated inhibition was
reduced twofold to threefold in the presence of IL-10, the inhibitory
effect of IL-10 was more evident on the total population where the
reduction was sixfold to sevenfold. This indicates that the IL-10
effect may require and/or is potentiated in the presence of
CD4+ cells. This finding is interesting in light of a
recent report where IL-10 was shown to drive the generation of
CD4+ clones that suppress antigen-specific
responses.14
Our results support the idea that IL-10 plays a pivotal role in the
establishment and maintenance of EBV carrier state through its ability
to enhance transformation of B cells during an initial infection and to
suppress the immune responses triggered by primary infection or during
subsequent reactivation of the virus. In the strategy of persistence of
herpes viruses, a reactivation step is required for spread to a new
host. This reactivation occurs in immunocompetent individuals. The
inhibitory mechanisms evolved by the viruses are partial and allow
delay of rejection until the productive virus cycle is completed.
During primary infection, the EBV replication is rapidly controlled by
a vigorous T-cell response, which includes CTLs specific for various
antigens of the lytic cycle.44, 45 The presence of vIL-10
and the virally induced hIL-10 may delay or partially reduce such
response so that the number of virally infected cells may reach a
sufficiently high level, before the onset of the rejection response, to
secure the access of the virus to an immunologically protected latent
reservoir. IL-10 was reported to prevent the apoptotic death of T cells
from infectious mononucleosis patients in vitro.46 This
promoting activity on the survival of T cells may be instrumental in
allowing the establishment of immunological memory after resolution of
the illness.
The inhibitory effect of IL-10 on EBV-specific memory response reported
in this study could also play an important role in viral pathogenesis.
The IL-10 effect on preventing T-cell reactivation could be one of the
mechanisms underlying the local suppression of EBV-specific T-cell
responses that we have shown in HD biopsies.47 In addition,
the combined effects of IL-10 described above may be responsible for
the association of IL-10 production and conditions of
lymphoproliferation such as lymphomagenesis in SCID-hu mice, AIDS-associated lymphomas, and HD.6-9,20,27
| |
ACKNOWLEDGMENT |
We thank Dr Rene de Waal Malefyt (DNAX Research Institute, Palo Alto,
CA) for the generous gift of IL-10.
| |
FOOTNOTES |
Submitted December 17, 1997;
accepted July 29, 1998.
Supported by the Swedish Cancer Society, the Lars Hiertas Minne
Foundation, the Gunnar Arvid and Elisabeth Nilsson Foundation, and the
Karolinska Institute.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to M.T. Bejarano, MD, MTC,
Karolinska Institutet, Box 280, S-171 77 Stockholm, Sweden; e-mail:
maria.teresa.bejarano{at}mtc.ki.se.
| |
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Abstract
Introduction