By
From The Rockefeller University, New York 10021
Diverse mechanisms are used by viruses to inhibit,
block, or evade the immune response (see review in
reference 1). These include reduced expression of critical
antigenic epitopes (e.g., EBV in latency), genetic variation
of class I-restricted CTL epitopes (HIV-1), clonal exhaustion
of CTLs (HIV-1, lymphocytic choriomeningitis virus),
downregulation of MHC class I and peptide-MHC complex expression (HSV, adenovirus, cytomegalovirus), production
of an immunosuppressive cytokine (e.g., IL-10-like factors
by EBV), and downregulation of critical cytokines such as
IL-12 (measles virus, HIV-1).
Three studies, two published in this issue of The Journal
of Experimental Medicine, describe a new mechanism
whereby virus infection can subvert the immune response
(2). Measles virus (MV) infection induces dendritic cell
(DC) apoptosis and syncytia formation, leading to profound inhibition of IL-12 production by DCs and T cell
proliferation. These studies may therefore provide some
explanation for the dramatic immunosuppression that is often observed during MV infection. In addition, they highlight the dual and contrasting roles of DCs as potentiators
of antiviral immune responses versus facilitators of disease
pathogenesis and immunosuppression.
Characteristics of MV Infection
MV is acquired through the respiratory epithelium
where it replicates and disseminates throughout the lymphoid system (5). MV binds to a surface receptor, CD46,
one of the regulators of complement activation via hemagglutinin (HA), and then fuses with the cell membrane via
its fusion (F) protein (6). Syncytia or multinucleated giant
cells (Warthin-Finkeldy cells) have been identified in the
submucosal regions of the tonsils and pharynx (7), and may
be a source of MV that spreads to other organs and tissues
throughout the blood stream.
In healthy children, measles infection is generally self-limited, causing primarily a rash and fever. Complications
include an otitis media, pneumonia, gastroenteritis, and
rare central nervous system syndromes including a postinfectious encephalitis and a delayed subacute sclerosing panencephalitis (5). MV infection can be complicated by a period of immunosuppression that can lead to secondary
infections by bacteria and fungi (8). This is especially significant in developing countries where malnutrition compounds the morbidity associated with these opportunistic
infections. Marked and prolonged abnormalities of cell-mediated immunity have been described. They include T
cell lymphocytopenia (9), inhibition of delayed-type hypersensitivity responses (10), suppression of recall responses
or proliferation to mitogen or alloantigens (11, 12), suppression of antibody production (13), and cell cycle arrest
of lymphoid cells in the G1 phase (11, 12). There may also
be skewing of the T helper response towards the Th2 phenotype (14). Cell-mediated immunity appears to be critical
in controlling measles infection. Both CD4+ and CD8+
cells have been implicated in the elimination of measles virus, but it is thought that the humoral response is required for
reducing viral load (5).
Several sources of DCs have been investigated: mature cells grown from cord blood progenitors
in GM-CSF and TNF (3), skin Langerhans cells (3), mature
circulating blood DCs (4), and immature DCs derived
from blood monocytes exposed to GM-CSF and IL-4 (2).
All DC sources were shown to be productively infected
with MV, including the Halle and Edmonston strains. 40- 100% of DCs infected at multiplicities of infection (MOIs)
of 0.05-0.1 expressed the viral proteins HA and F. Infectious particles were produced, albeit at low levels, 2 × 103
PFU/106 DCs. A small proportion of DCs formed syncytia. However, DC integrity and viability became grossly
compromised after a 3-4-d culture, secondary to apoptosis,
with death approaching levels of 45-70%. All apoptotic
APCs expressed nucleoprotein (NP; reference 2). Monocytes produced similar levels of infectious virus to DCs
(peaking at day 5 after infection), and also died from apoptosis but did not form syncytia (2).
When MV-infected DCs were cocultured with T cells, a
number of striking observations were made. First Fugier-Vivier et al. (2) showed that addition of PMA/ionomycin-activated T cells increased MV production in DCs up to
18-fold. In contrast, infection in monocytes was only increased
4-fold. Second, syncytia formation increased 7-15-fold.
The effects were evident shortly (1-2 d) after DC-T cell
coculture. Third, although viral replication occurred primarily in DCs (40-50% NP+) versus T cells (10% NP+),
dramatic levels of apoptosis were evident in both APCs and T cells, leading to 90% cell death by 7 d of coculture. It is not known whether the apoptosis is secondary to the expression of TNF-R superfamily and their ligands, including
fasL and fas, as described in HIV-1 infection (15).
All three studies demonstrated that T cell proliferation was markedly diminished in cocultures of MV-infected DCs and T cells. Fugier-Vivier et al. (2) found that the effect was evident early in the T cell response (1-2 d). The enhanced production of MV and syncytia formation induced in DCs upon
contact with T cells was dependent upon CD40, as it could
be significantly blocked by anti-CD40L Ab or mimicked
with CD40L-transfected fibroblasts (2). Furthermore, IL-12
production by MV-infected DCs was abrogated by 70%.
Since DCs are normally induced to synthesize IL-12
through CD40 signaling (16, 17), this suggests that independent pathways triggered by MV infection abrogate this effect. Indeed, it has recently been demonstrated that antibodies to CD46 can inhibit IL-12 production (18). Curiously,
UV-irradiated MV partially inhibited cell proliferation
(30%) and IL-12 production (20-30%), but did not induce
apoptosis of DCs or T cells or syncytia formation (2).
Using a different system, Grosjean et al. (3) demonstrated
that the ability of DCs to stimulate naive, CD45RA+,
CD4+ T cells in the allogeneic mixed leukocyte reaction
was completely abrogated after MV infection. As few as
30-100 infected cells caused substantial inhibition (>90%)
of proliferation by 2 × 104 T cells. Only a 1-h contact was
sufficient and, although there was progressive loss of DC
viability, T cell viability was not compromised. These findings differ from Fugier-Vivier et al. (2) in that the latter observed extensive death of T cells. One reason for this may be
that Grosjean et al. used mature DC populations. Mature
DCs are less efficient at permitting HIV-1 replication than
immature cells and may also be less permissive for MV
(Granelli-Piperno, A., E. Delgado, V. Finkel, W. Paxton,
and R. Steinman, manuscript submitted). Furthermore,
these investigators used naive CD45RA+ cells rather than
preactivated cells.
Some of
the mechanisms postulated to account for MV-induced immunosuppression here have been described before, although with other cells and not DCs as APCs. For example, Schendler et al. (19) showed that proliferation of PBLs
in response to a variety of stimuli was significantly impaired
after cocultivation with MV-infected, UV-irradiated autologous blood lymphocytes or monocytes. Direct cell-cell
contact rather than inhibition by direct virus infection or
release of an inhibitory factor was required. Both the MV
HA and F proteins appeared to be critical as coexpression of both, but not the individual proteins, in nonlymphoid
cells was necessary to suppress T cell proliferation.
Karp et al. demonstrated that MV infection efficiently
downregulated IL-12 production in primary human monocytes (18). Relatively few monocytes (<3% of the total
number) needed to be productively infected with MV for
inhibition of IL-12 production after stimulation with LPS
or staphylococcus Cowan strain 1 plus IFN- Finally, B cells also succumb to the effects of MV. In an
earlier issue, Ravenel et al. (20) reported that recombinant
MV NP directly binds to FcR How do these observations
reconcile the clinical descriptions of immunosuppression
after MV infection and the primary role of DCs as stimulators of immune responses? One interesting possibility is that
the giant multinucleated cells (Warthin-Finkeldy cells) in
the submucosal areas of the tonsils and pharynx are syncytia consisting of DCs and T cells. The DCs that line the mucosal surfaces where there are also many T cells, are the
most likely target cell candidates during viral transmission,
as suggested for HIV-1 (21). DCs are an important component of the protective immune response to microbes. Strategically located (lungs, skin, gut, liver), DCs are also recruited into the airway epithelium during the inflammatory
response to a broad spectrum of stimuli (22). Thus, DCs
may be a reservoir for MV infection and a vehicle to transmit the virus to lymphoid cells in draining nodes. It remains to be seen whether DCs can also mediate protective
immunity to MV.
DCs as APCs for Antiviral, T Cell-mediated Immunity
In murine systems, DCs were shown to be the most effective APCs for stimulating recall CTL responses to Sendai
virus (23), Moloney leukemia virus (23), HSV (24), and influenza virus (25). However, these studies used viruses simply as antigens to illustrate the potency of DCs to induce
CD8+ CTL responses.
More recent analyses with human cells have monitored
the viral life cycle in DCs. One example is influenza virus.
Exposure of DCs to influenza virus at MOIs of 2-4 leads to
>90% infection, as manifested by expression of the viral
proteins HA and nonstructural protein 1 (26). The infection is nontoxic, as viral protein expression is sustained for
>2 d with retention of viability. However, little infectious
virus is produced. DCs also synthesize substantial amounts
of IFN- Infected DCs, but not macrophages or B cells, can induce
substantial recall CTL responses from purified blood CD8+
T cells (26). Three pathways for presentation of influenza antigens to CD8+ CTLs by DCs have been identified.
Relatively few DCs are required to
generate CTL responses (stimulator/responder ratios of 1:
50-100) and low levels of infection (MOI of 0.02) are sufficient to generate potent CTLs (26). In contrast, infected
monocytes are inactive in inducing these CTL responses,
but can serve as targets for the CTLs that are induced by DCs.
DCs pulsed with poorly replicating
heat- or UV-inactivated influenza virus induce equally
strong CTL responses to DCs pulsed with live virus (27).
When pulsed with inactivated virus, <1% of DCs express viral protein, including nonstructural protein 1 (which is only
synthesized in the infectious cycle), indicating that only small
amounts of viral antigen are required by DCs to stimulate T
cells (27). The binding and fusogenic functions of inactivated
influenza virus are intact as assessed by standard hemagglutinating (binding) and hemolytic (fusion) assays. To be optimally effective, the inactivated virus must retain its fusogenic activity to presumably access the cytoplasm of DCs.
Monocytes and Hela cells
undergo apoptosis after infection with influenza virus, and
can be phagocytosed by uninfected DCs. It has now been
shown that DCs process viral antigens from the apoptotic
cells and acquire the capacity to induce virus-specific CD8+ class I-restricted CTL responses (Albert, M., B. Sauter, and N. Bhardwaj, manuscript submitted). This pathway may account for the phenomenon of cross-priming in
animal models, whereby antigens from donor cells could be
presented by host bystander cells (28).
The role of DCs in stimulating influenza-specific responses may be physiologic since DCs are residents of airway epithelia and can be rapidly recruited here after exposure to pathogens (22).
DCs in Viral Pathogenesis
The HIV-1 system best illustrates the dual role of DCs
during virus infection. DCs express the coreceptors required for the entry of HIV-1, that is, CD4 and several
chemokine coreceptors like CXCR4 and CCR5 (29).
When exposed to low levels of HIV-1, blood-derived DCs
transmit a vigorous cytopathic infection to CD4+ T cells
which is characterized by syncytia formation, virion release,
and T cell death by apoptosis (30). This is also the case
for DCs derived from human skin (33).
There are three striking features of this system. First,
DCs exposed to HIV-1 or carrying a relatively low level of
proviral DNA, promote extensive viral replication upon
interaction with syngeneic T cells in vitro (33, 34). Infectivity of mature DCs alone, either blood or skin, with
HIV-1 is low, however, with few full-length reverse trancripts detectable after infection. After a pulse with MOI of
0.05-0.1, <100 copies of full-length transcripts are detected by PCR per 5 × 104 cells. This low level of infection persists for at least 5 d in vitro and is <10-100 fold less
than seen with activated T cells (34). Second, infection in
this DC-T cell system is independent of antigens or exogenous stimuli such as IL-2. Third, the syncytia that form are
heterokaryons of DCs and T cells and are the sources of viral p24 and virion production. Eventually, cell death of the
memory T cells ensues (33, 34).
Cells expressing HIV-1 gag proteins have been detected
at the surfaces of mucosal lymphoid tissue, specifically the
nasopharyngeal tonsil or adenoid. The cells are comprised
of multinucleated syncytia expressing the S100 DC marker
(21). Memory T cells traffic through extravascular spaces
and can encounter tissue DCs in mucosal sites. Exposure to
virus here would permit active replication when both cells
interact with death of memory T cells. Thus, DCs may directly contribute to viral transmission, disease pathogenesis,
and the high level of CD4+ T cell death.
DCs could also have a role in eliciting CD8+ anti-HIV-1
responses. Given the ability of DCs to present inactivated
influenza virus or infected cells undergoing apoptosis (see
above), it is possible that they might present defective
HIV-1 (the majority of virus in plasma) or apoptotic CD4+
T cells to CD8+ T cells. So DCs at sites of viral replication
may represent a double-edged sword, promoting HIV-1
replication and inducing antiviral resistance.
As Fugier-Vivier et al. point out (2), the effects of MV
infection are curiously reminiscent of infection with HIV-1
where (a) only small amounts of virus are necessary to infect DCs (34), (b) low numbers of infected DCs induce extensive HIV-1 replication in cocultures of activated or
memory T cells (33), possibly via CD40L (35), (c) apoptosis
is induced in infected and bystander cells (15, 31), (d) there
is reduced capacity to synthesize IL-12 (36), (e) syncytia
form and are sites of extensive viral replication (30, 32, 33),
and (f) virus-infected syncytia are prominent in the epithelium of oral lymphoid tissue (21).
The study of viral life cycles in APCs is leading to a new
appreciation of the role of DCs in both protective and
pathogenic aspects of viral infection. In influenza, new
pathways for charging MHC class I molecules on DCs have
been ascertained, in HIV-1 infection, routes for virus transmission have been identified, and in measles infection, new
but still undefined pathways for immunosuppression have
been discovered.
. However, productive infection was not required for the effect, since
pulsing with UV-inactivated MV also suppressed IL-12
synthesis. The mechanism of suppression was considered to
be directly due to CD46 cross-linking, since incubation of
CD46 with specific monoclonal antibodies or dimerized
C3b directly blocked IL-12 production by LPS or staphylococcus Cowan strain 1 plus IFN-
.
II on B cells and inhibits
polyclonal Ig production by as much as 50%. Thus, MV
appears to affect a multitude of cells and cellular functions
that lead to suppression of both cell-mediated and humoral
immunity.
after infection, >3 ng/ml per 106 cells (Bender,
A., M. Albert, A. Reddy, B. Sauter, G. Kaplan, W. Hellman, and N. Bhardwaj, manuscript submitted). Influenza infection of macrophages also results in viral protein expression in a majority of cells (70%), and synthesis of IFN-
.
In contrast to DCs, however, macrophages begin to undergo apoptosis within 6-10 h, and most cells die within
24-36 h. During this interval macrophages synthesize low to
moderate levels of virus (Bender, A., M. Albert, A. Reddy,
B. Sauter, G. Kaplan, W. Hellman, and N. Bhardwaj,
manuscript submitted).
Address correspondence to Nina Bhardwaj, The Rockefeller University, 1230 York Ave., New York, NY 10021. Phone: 212-327-8332; FAX: 212-327-8875; E-mail: bhardwn{at}rockvax.rockefeller.edu
Received for publication 31 July 1997.
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