Download Virus interactions with dendritic cells

Journal
of General Virology (1999), 80, 823–833. Printed in Great Britain
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Virus interactions with dendritic cells
Ingo M. Klagge and Sibylle Schneider-Schaulies
Institute for Virology and Immunobiology, University of Wu$ rzburg, Versbacher Str. 7, D-97078 Wu$ rzburg, Germany
Introduction
Dendritic cells are bone marrow-derived cells that form a
system of professional antigen-presenting cells (APC). They
are located in most tissues and include Langerhans cells in the
skin and mucous membranes, dermal dendritic cells, tissueresident interstitial dendritic cells, interdigitating dendritic cells
in the thymic medulla and secondary lymphoid tissues and
veiled dendritic cells in the blood and lymph. Dendritic cells
capture and process antigen in the periphery and, as a result of
inflammatory signals, they migrate to T cell-rich areas of
lymphoid organs where they display MHC–peptide complexes, together with costimulatory molecules. This results in
the activation of naive and resting antigen-specific T cells.
Because of their unique property of activating naive T cells,
dendritic cells are believed to play a central role in initiating the
adaptive immune response against infecting agents. To
understand dendritic cell function and their interaction with
pathogens is, therefore, important for understanding lymphocyte priming, for manipulation of the immune response in
the early sensitization phase and for development of new and
more efficient vaccines. The presence of dendritic cells within
the skin, the blood and particularly within the mucosal surfaces
identifies them as one of the cell populations most likely to
have the earliest contact with viruses during infection. Thus,
dendritic cells may not only be involved in triggering primary
antiviral immune reactions, but also in the propagation of viral
infection. Consequently, they may, indeed, contribute to the
pathogenesis of viral disease. This review will focus on the role
of dendritic cells using two examples of chronic and acute,
self-limiting viral infections ; namely AIDS and measles,
respectively.
Origin and functional properties of dendritic
cells
The dendritic cell lineage is very complex and has several
subsets and maturation stages (reviewed in Knight & Patterson,
1997 ; Bancherau & Steinman, 1998). Dendritic cells develop
from at least one myelomonocytic and one lymphoid precursor. The former gives rise to Langerhans cells, dermal
dendritic cells and interstitial dendritic cells, all of which are
Author for correspondence : Sibylle Schneider-Schaulies.
Fax j49 931 201 3934. e-mail s-s-s!vim.uni-wuerzburg.de
found in peripheral tissues (Caux et al., 1996). Dendritic cells of
lymphoid origin are found in primary and secondary lymphoid
tissues and are involved in negative selection during thymocyte development and in the downregulation of primary
peripheral T cell responses (Suess & Shortman, 1996 ; Vremec
& Shortman, 1997 ; Grouard et al., 1997 ; Kronin et al., 1996 ;
Inaba et al., 1997). It was only after the development of
purification protocols and the establishment of appropriate
tissue culture systems that the maturation of dendritic cells and
their biological properties could be studied in vitro. Thus, for
the human system, dendritic cells are directly isolated from skin
explants (as Langerhans cells) or peripheral blood. Alternatively, dendritic cells can be generated in vitro from CD14+
peripheral blood monocytes or CD34+ cord blood stem cells in
the presence of cytokines such as GM–CSF, IL-4 and TNF-α
(Caux et al., 1997 ; Bender et al., 1996 ; Romani et al., 1996 ;
Zhou & Tedder, 1996).
Dendritic cells exist in an immature or mature state
(reviewed in Banchereau & Steinman, 1998). Immature dendritic cells are found at body surfaces and in the interstitial
spaces of most tissues. For instance, humans have about 10*
epidermal Langerhans cells which are located above the basal
layer of proliferating keratinocytes. They are equipped to
capture antigens by macropinocytosis and receptor-mediated
endocytosis (Sallusto et al., 1995 ; Tan et al., 1997 ; Engering et
al., 1997). Immature dendritic cells are characterized by
intermediate levels of MHC class II molecules, low levels of
costimulatory molecules such as CD80 and CD86, intermediate
levels of CD1a and the absence of CD83, which is expressed
only on mature dendritic cells and B cell blasts (Zhou & Tedder,
1995 a, 1996). Consistent with this surface-protein expression
pattern, immature dendritic cells are poor stimulators of T cell
immunity. This is reflected in vitro by their low capacity to
stimulate an allogeneic T cell proliferative response in a mixed
lymphocyte reaction (MLR).
After infection or inflammation, signals are delivered which
induce the full maturation and mobilization of immature
dendritic cells (Henderson et al., 1997 ; Jonuleit et al., 1997 ;
Ojcius et al., 1998). Peripheral dendritic cells, particularly those
from the skin, the lungs and the gut or genital mucosa, carry
antigen into the lymph nodes where they appear as mature
interdigitating dendritic cells within the T cell-dependent areas
(Ingutti et al., 1997). Interdigitating dendritic cells no longer
process antigen but increase their T cell-stimulatory capacity
by upregulating adhesion and costimulatory molecules (McICD
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I. M. Klagge and S. Schneider-Schaulies
Lellan et al., 1995, 1996). Numerous intracellular MHC class II
compartments release MHC class II–peptide complexes to the
cell surface (Cella et al., 1997 ; Pierre et al., 1997). As a result,
cognate T cells are clonally expanded and a T cell immunity of
both the Th1 and Th2 type is induced. For CTL responses,
cooperation between antigen-specific Th1 and cytotoxic T
cells is essential. This is brought about by an antigen-loaded
dendritic cell that displays antigens to both helper and
cytotoxic T cells (Schoenberger et al., 1998 ; Ridge et al., 1998 ;
Bennett et al., 1998). The first step (help) can be bypassed by
viral infection of dendritic cells (Ridge et al., 1998). Dendritic
cells are not found in the efferent lymph. They are thought to
die in the lymph nodes by an as yet undefined mechanism. This
elimination process might act as a feedback for removing
the activation stimulus for immune responses (Knight et al.,
1997 a, b).
Mature dendritic cells have the unique ability to nonspecifically attract and aggregate naive T cells by producing a
variety of chemokines (Zhou & Tedder, 1995 b ; Ghanekar et al.,
1996 ; Adema et al., 1997) Thus, they are able to stimulate
primary T cell responses. In contrast, macrophages and other
tissue cells bearing MHC molecules are involved mainly in the
expansion of activated T cells. A major criterion of dendritic
cell maturation in vitro is their high MLR stimulatory activity.
In vivo and in vitro, only a few dendritic cells are necessary to
provoke a strong T cell response. Typically, only one dendritic
cell is required to stimulate 100–3000 T cells in an MLR. The
potency of these cells in T cell binding and activation does not
appear to be attributable to a specific molecule. The characteristic effects of dendritic cells seem rather to relate to
quantitative aspects. For example, the surface expression levels
of MHC products and MHC–peptide complexes on dendritic
cells are 10–100 times higher than on other APC such as B cells
and monocytes (Inaba et al., 1997). Mature CD83+ dendritic
cells, which are morphologically characterized by large veils of
sheet-like processes, also express high levels of costimulatory
molecules that interact with receptors on T cells to enhance
adhesion and signalling. Furthermore, mature dendritic cells
produce high levels of IL-12 upon activation with LPS or after
CD40 ligation (Macatonia et al., 1995 ; Cella et al., 1996 ;
Heufler et al., 1996 ; Koch et al., 1996). Interleukin-12 is
critically involved in the generation of a protective Th1
response and the generation of cellular immunity. Following
systemic LPS administration, dendritic cells have been identified as the major producers of IL-12 in lymph nodes, thus
shaping the T cell immunity towards a Th1-type response
(Sousa et al., 1997).
The role of dendritic cells in stimulating
antiviral immune responses
In murine systems, dendritic cells have been shown to be
the most effective APC for the stimulation of recall CTL
responses to Sendai virus, Moloney leukaemia virus (Kast et al.,
ICE
1988), herpes simplex virus (Hengel et al., 1987) and influenza
virus (Nonacs et al., 1992). These studies used viruses simply as
antigens to illustrate the potency of dendritic cells in relation to
the induction of CD8+ CTL responses. The power of dendritic
cells to induce protective immune responses against viral
infection has also recently been demonstrated by adoptive
transfer, either with dendritic cells pulsed with the lymphocytic
choriomeningitis virus (LCMV)-specific peptide GP33–41, or
dendritic cells that constitutively express the same epitope
(Ludewig et al., 1998). In this system, only 100–1000 dendritic
cells had to reach the spleen to achieve protective levels of
CTL activation, which developed 2–4 days after immunization
and were still demonstrable after 60 days. Since mice
immunized with dendritic cells were also able to rapidly clear
a recombinant vaccinia virus–LCMV infection from the ovaries
and were able to eliminate LCMV from the brain (thereby
avoiding lethal choriomeningitis), it is clear that priming with
dendritic cells also confers protection against infections in
which the homing of CTL into peripheral organs is essential. In
a similar fashion, infection with influenza A virus has been used
extensively to characterize the role of dendritic cells in
stimulating primary and secondary antiviral T cell responses,
both in vivo and in vitro. In these studies, macrophages,
dendritic cells, and to a very limited extent B cells, were
identified as virus-antigen-positive APC in the lungs and
mediastinal lymph nodes of intranasally infected mice. Dendritic cells were also found to be pivotal for initiating the CTL
response to influenza virus in the draining lymph nodes
(Hamilton-Easton & Eichelberger, 1995).
The exposure of human dendritic cells to influenza virus in
vitro leads to efficient infection, as shown by the expression of
the viral HA and NS1 proteins (Bender et al., 1998). The
infection does not, however, lead to rapid cell death. Indeed,
viral protein expression is maintained for more than 48 h with
the retention of cell viability. Also, little infectious virus is
produced. Moreover, in these cultures, a substantial induction
of IFN-α occurs and apoptosis is not observed. This is in
contrast to, for example, human macrophages infected with
influenza A virus, where higher levels of virus are released,
apoptosis occurs within 10–12 h and the majority of cells die
within 24–36 h. Also, infected dendritic cells, but not macrophages, can induce substantial CTL responses from purified
blood CD8+ T cells in the absence of exogenous cytokines
such as IL-2.
De novo viral protein synthesis is not required to charge
MHC class I molecules on dendritic cells. Dendritic cells pulsed
with replication-incompetent virus (after heat- or UV-inactivation) induce an equally strong CD8+ CTL reaction in the
absence of CD4+ helper T cells and exogenous cytokines.
Apparently, the inactivated virus needs only to retain its
fusogenic activity to be effective, and presumably needs to
access the cytoplasm of dendritic cells. Thus, dendritic cells
require only small amounts of viral proteins to charge MHC
class I molecules, most likely via traditional class I-processing
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pathways (Bender et al., 1995). There is, however, also evidence
for an exogenous pathway, whereby antigens that are not
expected to gain access to the cytoplasm are presented on
MHC class I molecules. The most dramatic example of this
exogenous pathway is the in vivo phenomenon of crosspriming. In this situation, antigens from donor cells are acquired
by bone marrow-derived host APC and presented on MHC
class I molecules. Using influenza A virus-infected macrophages the cross-priming of human dendritic cells and
subsequent stimulation of influenza A-specific class I-restricted
CD8+ T cells has been shown (Albert et al., 1998 a). The
phagocytosis of apoptotic cells was found to be restricted to
immature dendritic cells and to be dependent on CD36 and
α β integrin expression (Albert et al., 1998 b). The transfer of
v &
antigen between dendritic cells, leading to an antigen gradient
within the dendritic cell population, may even be essential for
an efficient stimulation of primary T cells (Knight et al., 1998).
Once efficiently generated, a virus-specific CTL response may
act as a feedback mechanism for removing dendritic cells after
they have stimulated T cell responses. This has been shown for
the CTL-mediated killing of influenza A virus- or human
immunodeficiency virus (HIV)-infected dendritic cells in vitro
(Knight et al., 1997 a, b).
The role of dendritic cells in viral
pathogenesis
Viruses can directly or indirectly modulate dendritic cells
and thus interfere with immune responses. Since dendritic cells
are the primary APC for the activation of CTL responses, and
CD4+ T cells provide help for long-term CD8+ CTL activity,
interference with either dendritic cells or CD4+ cell types
constitutes one mechanism that viruses can exploit to disable
the immune response. Cells of the dendritic lineage are thought
to be among the first cells infected after mucosal exposure to
a variety of viruses. The HIV system best illustrates the dual
role of dendritic cells during virus infection. On the one hand,
the uptake of virus, the processing of viral proteins and the
presentation of viral antigens efficiently trigger both virusspecific CD4+ and CD8+ T cell responses, whilst, at the same
time, dendritic cells serve as vehicles to transport live virus into
lymph nodes and thereby contribute to the transmission of
virus to T cells and to the pathogenesis of the disease
(reviewed in Knight & Patterson, 1997).
The role of dendritic cells in retroviral infections
Virus uptake in dendritic cells and their role in transmission.
There is substantial evidence that during sexual transmission of
HIV and simian immunodeficiency virus (SIV) dendritic cells
residing within the epithelial surfaces (such as Langerhans cells
in the vaginal epithelium) and dendritic cells or macrophages in
the lamina propria are the cells initially infected. Thus, whilst
SIV-infected macrophages are rarely found in the genital tract
after experimental infection, infection of Langerhans cells and
dendritic cells in the genital tract and lymph nodes has been
directly demonstrated. This confirms that dendritic cells in
general, and Langerhans cells in particular, are important
reservoirs for HIV\SIV in vivo (Hu et al., 1998) and they may
serve to as vehicles to transport these viruses to the lymph
nodes (Masurier et al., 1998). This conclusion is also supported
by data showing that the infection of blood dendritic cells
increases with the progression of AIDS (Patterson et al., 1994).
The distribution of dendritic cells at mucosal surfaces, in the
skin and in the blood marks them as potentially important
vehicles of transmission for a wide range of viral infections.
M-tropic strains of HIV-1 are predominant during the
initial viraemia phase after person-to-person transmission. This
selection may occur during the entry of virus into specific cells,
including the dendritic cell population, or during the carriage
of virus to the lymphoid tissue. Since the surfaces of the vagina,
cervix and anal canal are histologically similar to skin, human
skin explant models have been used as a model to study the
uptake of HIV-1 by dendritic cells. These studies show that
whilst there is some evidence to suggest that selective infection
of immature epidermal dendritic cells may represent the cellular
mechanism restricting initial infection (to CCR5 coreceptor
utilizing strains), dermal dendritic cell emigrants are able to
support the uptake of both M- and T-tropic strains (Reece et al.,
1998). In vitro, monocyte-derived dendritic cells, dendritic cells
cultured from precursors, or emigrant dendritic cells from the
skin also showed little or no selectivity for virus entry.
Dendritic cells express CCR5 and this may be used for the
entry of M-tropic isolates, the uptake of which is blocked by
RANTES, MIP1α, MIP1β, eotaxin, MCP-1 and MCP-4. CCR3
is also expressed on dendritic cells and may be used as a
coreceptor by certain dual-tropic strains. The expression of
CXCR4 on dendritic cells is somewhat controversial (Ayehunie
et al., 1997 ; Rubbert et al., 1998). Thus, dendritic cells are
susceptible to infection with T-tropic HIV which can be
inhibited by stromal cell-derived factor 1 (SDF-1) and anti-fusin
antibodies, and the treatment of dendritic cells with SDF-1
induces a calcium flux. Since dendritic cells from individuals
homozygous for a 32 bp deletion of the CCR5 gene can also
be infected with M-tropic strains of HIV-1, and this infection is
inhibited by SDF-1, this receptor can apparently also be used
by M-tropic HIV (Rubbert et al., 1998).
HIV replication in dendritic cells and dendritic cell–T cell
conjugates. The developmental stage of dendritic cells can
influence their interaction with HIV-1 and the extent to which
M- and T-tropic virus can replicate (Compton et al., 1996,
Warren et al., 1997). Thus, mature dendritic cells do not
support replication of HIV-1, whereas immature dendritic cells
can be productively infected with M-tropic strains. The
replication block in mature dendritic cells appears to be at the
level of reverse transcription. In contrast, immature dendritic
cells cultured in GM–CSF and IL-4 complete reverse transcription. The virus produced by immature dendritic cells
readily infects activated T cells. Although mature dendritic
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I. M. Klagge and S. Schneider-Schaulies
cells do not produce virus, these cells can transmit virus to T
cells (Granelli-Piperno et al., 1998).
Dendritic cells may be early targets of HIV infection and,
by clustering T cells, they may disseminate the virus and
contribute to the loss of cells by infection. Dendritic cells
exposed to HIV-1, or those carrying relatively low levels of
proviral DNA, promote extensive virus replication in combination with syngeneic T cells in vitro. The capacity to
transmit HIV to T cells is lost approximately 24 h after
exposure, which could be due to the processing and breakdown
of infectious virus particles. Blood dendritic cells, when
exposed to low levels of HIV-1, transmit a vigorous cytopathic
infection to CD4+ T cells which is characterized by syncytium
formation, virion release and T cell death by apoptosis.
Similarly, the low level of HIV-1 produced from monocytederived dendritic cells is strongly enhanced after cocultivation
with autologous resting CD4+ T cells (Pope et al., 1994, 1995).
Direct contact between both populations is crucial for
transmission and subsequent virus production and this is
prevented by blocking the LFA-1\ICAM-1 or LFA-3\CD2
interaction. Since virus production from infected dendritic cells
is also enhanced by cross-linking CD40, both adhesion and
mutual activation of HIV-1-infected dendritic cells and T cells
may potentiate virus transmission and production (Tsunetsugu-Yokata et al., 1997). The efficient activation of T cells and
the induction of a productive infection are also observed with
human cultured skin dendritic cells, even with low levels of
HIV infection. Mature Langerhans cells, the ex vivo correlate of
interdigitating dendritic cells, are susceptible to infection with
HIV-1, they readily cluster T cells and they efficiently transmit
the virus to CD4+ T helper cells. In the cluster of infected
Langerhans cells and activated T cells, massive HIV production
occurs which leads to the subsequent elimination of the
activated and infected CD4+ T cells (Ludewig et al., 1996). The
formation of such dendritic cell–T cell conjugates during
migration from the skin may allow efficient transfer of virus
from Langerhans cells and be critical in the initial transfer of
virus to responding T cells. The observation of dendritic cellderived syncytia in T cell-rich areas near the crypts of the
oropharyngeal lymphoid tissue also implies that formation of
dendritic cell–T cell conjugates may represent sites of virus
production in vivo (Frankel et al., 1996).
The cutaneous or mucosal dendritic cell–T cell environments also seem to support HIV replication. Large amounts of
virus can be detected in the germinal centres of lymph nodes,
most of which comprises immune-complexed virus that is
trapped on follicular dendritic cells. Follicular dendritic cells are
found in the follicles of virtually all secondary lymphoid tissues
and are not related to bone marrow-derived dendritic cells.
These cells trap and retain antigens as immune complexes and
preserve them over a period of months in their native
conformation. Thus, they are long-term repositories of extracellular antigen and are important for the induction and
maintenance of memory responses. After primary infection,
ICG
acute viraemia occurs during which the virus is trapped within
the processes of follicular dendritic cells in the germinal centres
of the lymphoid tissue. Since follicular dendritic cells in lymph
nodes lack HIV coreceptor expression, the ability of these cells
to trap extracellular virions is unlikely to be mediated by a
coreceptor-specific mechanism (Zhang et al., 1998). It is unclear
whether virus is actually produced from these complexes. In
lymph nodes from HIV-infected individuals, the trapping of
HIV in the follicular dendritic cell network was minimal within
the first 3 months of the acute viral syndrome but was the
predominant form of HIV detected in lymph nodes of patients
with chronic infection (Pantaleo et al., 1998).
Functional consequences of HIV interactions with dendritic cells
or dendritic cell–T conjugates. Once acquired by dendritic cells,
viral antigens may be presented within the draining lymph
nodes to produce immune responses. Thus, blood dendritic
cells exposed to HIV (or to viral antigens) in vitro can initiate
primary T cell proliferation and CTL responses which kill virusinfected cells. In the natural infection, however, a reduction in
the numbers of dendritic cells in the skin, the gut mucosal tissue
and in the peripheral blood of asymptomatic individuals (i.e.
before obvious changes in T cell numbers are seen), as well as
in AIDS patients, is observed. In symptomatic HIV-1-infected
patients, the proportion of dendritic cells in the mononuclear
cell population is reduced (Patterson et al., 1998).
Loss of dendritic cells during the course of HIV infection
may result from a block in dendritic cell development from
peripheral stem cells. Alternatively, the high levels of CTL
activity in patients infected with HIV may also contribute to
the loss of dendritic cells, particularly the loss of persistently
infected dendritic cells. It has been shown that HIV- or HIVpeptide-stimulated CTLs are able to lyse HIV-infected dendritic
cells in vitro. Interestingly, dendritic cells were found to be
largely refractory to CTL killing until they had been exposed
to virus for 2–3 days. This killing of dendritic cells 2–3 days
after infection may reflect a feedback mechanism for the
removal of APC after they have stimulated T cell responses
(Knight et al., 1997 a, b). CTL-mediated lysis of dendritic cells
has also been implicated in the pathogenesis of experimental
LCMV infection in mice (Borrow et al., 1995 ; Oldstone, 1997).
Additionally, syncytia formed between dendritic cells and T
cells may not only form a site of active virus replication but
could also provide a mechanism whereby functional dendritic
cells and T cells are removed by HIV infection.
Early in HIV infection, the stimulation of CD4+ T cell
proliferation is reduced. There is a time-dependent pattern in
the loss of T cell responsiveness with the response to recall
antigen disappearing first, followed by the response to
alloantigens (in an MLR) and then the mitogen response
(Clerici et al., 1989). In HIV infection, there are obvious
possibilities for the direct loss of infected T cells by lytic effects
of the virus and syncytium formation. Possibly of greater
significance, however, is the alteration in signalling between
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dendritic cells and T cells. Thus, dendritic cells isolated from
the peripheral blood of HIV patients stimulate primary
allogeneic T cell proliferation less efficiently. This is not only a
reflection of dendritic cell loss but also reflects the inability of
the dendritic cells to stimulate T cell proliferation, since resting
or naive T cells from HIV-infected patients responded normally
to stimulation by allogeneic dendritic cells from uninfected
individuals (Macatonia et al., 1992). A failure of Langerhans
cells to stimulate naive T cell responses has also been described
(Blauvelt et al., 1995).
The reduced ability of dendritic cells to stimulate T cell
proliferation in HIV infection can be reproduced by exposure
of dendritic cells to HIV for several days in vitro (Knight et al.,
1993 ; Macatonia et al., 1989). Also in the in vitro system, loss
of the capacity of dendritic cells to stimulate T cell proliferation
is not related directly to the level of infection. Thus, this effect
was not seen if blood dendritic cells were exposed to HIV,
even at high input multiplicities, for less than 2 days. In this
case, the dendritic cells were able to stimulate both primary
proliferative and CTL responses. However, after longer
exposure, particularly to high input multiplicities, the dendritic
cells showed little stimulation of T cells and transmission of
virus to T cells was minimal, although an increasing proportion
of the dendritic cells was infected. It is possible that infection
at a particular stage in the development of dendritic cells may
cause a defect in stimulation because dendritic cells derived
from CD34+ stem cells can show high levels of infection but
still maintain normal function (Knight & Patterson, 1997).
Since, in HIV infection, dendritic cells fail to stimulate primary
T cell reactions, CD4+ T cells may not be recruited efficiently
into the memory pool. This would result, together with the
infection and loss of T cells, in a loss of memory T cells in
infected individuals. Although the question has not been
directly addressed for HIV, the greater persistence of CTLs
may reflect the maintenance of the capacity of dendritic cells to
stimulate CD8+ T cells.
The altered function of dendritic cells was also shown to be
associated with the development of another retroviral-induced
immunosuppression. In Rauscher leukaemia virus (RLV)induced immunodeficiency, dendritic cells fail to migrate from
the skin into lymph nodes, following exposure to skin
sensitizers. Downregulation of CD54 and CD44 surface
expression (Gabrilovich et al., 1993, 1994 a, b), as well as MHC
class II gene transcripts, has also been observed (Gabrilovich et
al., 1996). In this model, both infection of dendritic cells and a
reduced capacity of these cells to stimulate CD4+ T cell
proliferation was found. T cells from RLV-infected mice
showed normal responses to allogeneic dendritic cells (Gabrilovich et al., 1993). Expression of MHC class I and the ability to
stimulate CD8+ T cells, however, was not impaired (Gabrilovich et al., 1996). Interestingly, treatment with IL-12 at the time
of infection resulted in dendritic cells that stimulated normal T
cell proliferation. The low dose of IL-12, which allowed normal
dendritic cell and T cell function, gave normal delayed-
hypersensitivity reactions in these animals (Williams et al.,
1998).
Measles virus–dendritic cell interactions
Measles still ranks as one of the leading causes of childhood
mortality in the world. In developing countries there are 30–40
million cases of measles reported each year and about 1 million
deaths are associated with MV infection. In 1995 measles was
listed among the ten most common (42 million cases) and ten
most deadly diseases (more than 1 million deaths) worldwide
(World Health Report 1996 ; reviewed in Clements & Cutts,
1995).
This high morbidity\mortality rate has been associated
with measles virus (MV)-induced immunosuppression. This
immunosuppression develops in the presence of a substantial
MV-specific humoral and cellular immune response, leading to
virus clearance and the establishment of a lifelong immunity
against reinfection. There is a strict correlation between the
extent of MV-specific immune activation and the level of
immunosuppression, both after natural measles and, to a more
moderate extent, after vaccination (Starr & Berkovitch, 1964 ;
Hussey et al., 1996). MV-induced immunosuppression is
generally characterized by loss of the delayed type hypersensitivity (DTH) skin test response to recall antigens and an
increased susceptibility to secondary infections (reviewed in
Borrow & Oldstone, 1995). At the same time there is a marked
lymphopenia affecting both B and T cells (of both the CD4 and
CD8 type) and the presence of MV-specific RNA and proteins
in a relatively small number of PBMCs (Arneborn & Biberfeld,
1983 ; Schneider-Schaulies et al., 1991 ; Esolen et al., 1993 ;
Nakayama et al., 1995). A hallmark of MV-induced immunosuppression is that PBMCs isolated during, and for several
weeks after acute measles, mostly fail to proliferate in response
to mitogenic, allogeneic and recall antigen stimulation in vitro.
MV is transmitted from the respiratory tract to the draining
lymph nodes. Virus amplification at these sites gives rise to
giant multinucleated lymphoid or reticuloendothelial cells (i.e.
Warthin–Finkeldey cells) in the submucosal areas of the tonsils
and pharynx. These are thought to be a major source of virus
spread to other organs and tissues through the bloodstream.
As outlined above for HIV, dendritic cells of the respiratory
mucosa may be the first target cells to encounter MV during
primary infection and subsequently they transport antigens to
the draining lymph nodes to initiate a virus-specific immune
response. Again, similar to HIV, MV interference with dendritic
cell functions may be central to the induction of MV-induced
immunosuppression.
MV replication in dendritic cells. The interaction of dendritic cells
with MV has been studied in vitro using skin Langerhans cells,
immature dendritic cells derived from blood monocytes,
freshly isolated peripheral blood dendritic cells and mature
dendritic cells grown from CD34+ cord blood progenitors (in
the presence of GM–CSF and TNF-α). Both immature precursor
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I. M. Klagge and S. Schneider-Schaulies
and mature dendritic cells obtained by these protocols were
highly susceptible to infection with MV and had high levels of
MV proteins both in their cytoplasm and on their surface
(Schnorr et al., 1997 a ; Fugier-Vivier et al., 1997 ; Grosjean et al.,
1997). As is the case with primary monocyte\macrophage
cultures, however, virus release from MV-infected dendritic
cells was inefficient, suggesting that virus transmission in
dendritic cell cultures may occur primarily in a cell-associated
manner. Interestingly, the replication of an MV wild-type
strain (WTF) proceeded significantly faster than the Edmonston
(ED) vaccine strain in both immature and mature dendritic cells
(Schnorr et al., 1997 a).
Similar to HIV, MV production and the formation of
syncytia in dendritic cell cultures was enhanced in the presence
of activated or memory T cells or after ligation by L cells
expressing CD40L. The transmission of MV to T cells,
however, was limited in the coculture (Fugier Vivier et al.,
1997). Apoptosis of infected dendritic cells and a large fraction
of both infected and uninfected T cells was observed in
cocultures, whereas apoptotic cell loss was markedly less
pronounced after dendritic cell infection alone (Grosjean et al.,
1997). It has not been resolved whether the apoptosis seen in
uninfected T cells is, as found for HIV, secondary to the
expression of the TNF-R superfamily and their ligands
(including FasL and Fas as described in HIV infection in
macrophages) or to the release of cytotoxic factors, as found
for human thymic dendritic cells (Badley et al., 1996 ; Beaulieu
et al., 1998). Syncytia generated by MV infection of skin
Langerhans cells or in vitro-generated dendritic cells may
represent the in vitro equivalent of the multinucleated giant
cells seen infiltrating the nasopharyngeal epithelium and the
subepithelial layer of tonsils during the prodromal stage of
measles.
Functional consequences of MV infection. Downregulation of
CD46, an MV receptor, was observed after infection of mature
dendritic cells with certain MV strains (Schneider-Schaulies et
al., 1995 ; Schnorr et al., 1997 a) whereas expression of specific
dendritic cell-surface markers was not altered. For immature
dendritic cells, a rapid maturation, as revealed by the
upregulation of HLA-DR, CD40, CD83, CD80 and CD86, was
observed after infection, concomitant with the expression of
viral glycoproteins. Conflicting results have been obtained on
the release of IL-12 from dendritic cell cultures after MV
infection. Whereas MV infection stimulated LPS- or SACS
(Staphylococcus aureus Cowan strain)-induced IL-12 synthesis in
one study (Schnorr et al., 1997 a), a significant inhibition of
CD40L-induced IL-12 release has also been described (FugierVivier et al., 1997). Inhibition of LPS- or SACS-stimulated IL12 release has previously been found in monocyte cultures
after engagement of CD46 by MV, its natural ligands (the
complement components C3b\C4b), or after ligation of Fcγ
receptor or scavenger receptors (Karp et al., 1996 ; Sutterwala
et al., 1997). The impact of MV on IL-12 release from dendritic
ICI
cells may be dependent on the source or maturation stage of
these cells as well as the strain of MV. In particular,
lymphotropic MV wild-type isolates fail to downregulate
CD46, and, as shown in recent studies, may not even use this
protein as an attachment receptor (Hsu et al., 1998 ; Bartz et al.,
1998).
As outlined for HIV, MV-infected dendritic cells largely fail
to induce an allostimulatory response when assayed in an
MLR, in spite of their activated phenotype (Fugier-Vivier et al.,
1997 ; Grosjean et al., 1997 ; Steineur et al., 1998). Moreover,
even the mitogen-dependent proliferation of PBLs was impaired in the presence of MV-infected dendritic cells (Schnorr
et al., 1997 a). Also, dendritic cells infected with wild-type MV
were found to afford stronger suppression, compared to those
infected with the vaccine strain of MV. The reasons put
forward to explain the loss of allostimulatory properties, or the
suppressive activities of MV-infected dendritic cells, include
the loss of both dendritic cells and T cells by apoptosis or cell
fusion, depletion of IL-12 or the transfer of MV from dendritic
cells to T cells (Fugier-Vivier et al., 1997 ; Grosjean et al., 1997).
However, it has been shown experimentally that contact
between the MV glycoproteins F and H (on the surface of UVirradiated infected cells, cells transfected with F\H expression
constructs or UV-irradiated viral particles) is sufficient to
induce a state of unresponsiveness towards mitogenic, allogeneic or anti-CD3-mediated stimulation in freshly isolated
human and rodent PBL (Schlender et al., 1996 ; Schnorr et al.,
1997 b). Thus, after contact with F\H-expressing cells, PBL did
not undergo apoptosis but rather accumulated in the G1 phase
of the cell cycle. Contact-mediated inhibition did not impair
the mitogen-induced upregulation of early activation markers,
including the IL-2R subunits, and proliferative arrest could not
be reverted by exogenous IL-2 (Schnorr et al., 1997 b). Thus,
since high levels of MV glycoproteins are expressed on the
surface of dendritic cells after infection, their inhibitory activity
might reflect a dominant negative signalling to T lymphocytes,
exerted by MV glycoproteins. In support of this hypothesis,
dendritic cells infected with a recombinant MV (MGV)
expressing the VSV G protein, instead of the MV glycoproteins, efficiently stimulated an MLR and did not inhibit
mitogen-dependent proliferation of human PBL (I. M. Klagge,
unpublished). There may, of course, be additional effects of
MV infection on specialized functions of dendritic cells, such as
alterations of cytokine reactivity or release, or on their ability
to capture, process and present antigen. Mannose-receptormediated endocytosis, however, was not impaired 2 days after
infection of dendritic cells by MV (Grosjean et al., 1997).
MV interactions with dendritic cells during natural measles or
experimental infection. So far, the role of dendritic cells during
natural measles has not been directly assessed. Study of this
particular interaction has been hampered by the lack of suitable
animal models, since mice and rats cannot be infected by the
intranasal route. However, following intranasal infection of
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Review : Viruses and dendritic cells
juvenile Rhesus monkeys, skin rash, pneumonia and systemic
infection with dissemination to further mucosal sites and to the
lymphoid tissue is observed (McChesney et al., 1997). Also,
inflammation and necrosis occurred in the lungs and lymphoid
tissues and many cell types, most frequently B cells in lymphoid
follicles, were infected with MV after 1 week. MV antigen was
found in follicular dendritic cells 14 days after infection. It is
unclear whether follicular dendritic cells would support virus
replication. The impact of infection on bone marrow-derived
dendritic cells has not been investigated in this system.
The role of dendritic cells during natural measles infection
is unknown. Since MV can replicate in dendritic cells generated
in vitro, and these cells are comparable to the immature
dendritic cells, the mature interdigitating dendritic cells, as well
as Langerhans cells in vivo, it is likely that natural measles
infection is initiated by the uptake and replication of MV
within epithelial Langerhans cells and dermal\interstitial
dendritic cells at mucosal membranes. Dendritic cells then
migrate to the T cell areas of lymphoid organs where they
present immunogenic peptides to naive T lymphocytes. This
interaction with T cells allows MV to undergo massive
replication, to some degree in syncytia, but predominantly in
dendritic cells. Once the expression of the viral glycoproteins
exceeds a certain threshold on the surface of dendritic cells,
these cells will probably deliver a negative signal to both
resting and activated T cells, which will contribute to the
suppression of T cell functions directed against opportunistic
infections.
Conclusions and perspectives
Because of their specialized properties, dendritic cells can be
considered as natural adjuvants that efficiently initiate immune
responses. This has been widely studied using model antigens
including viruses, where the role of dendritic cells in initiating
protective T cell responses has been convincingly demonstrated. Their location at mucosal surfaces and their ability to
take up antigen at these sites predisposes dendritic cells, and in
particular immature dendritic cells (such as Langerhans cells), to
function as primary target cells for viral infection. As outlined
above, dendritic cells are likely to be the major players in
initiating primary antiviral T cell responses. Although there is
evidence to suggest that virus infection can induce functional
maturation of dendritic cells directly, and thus substitute for
example CD40 ligation by activated T cells (Ridge et al., 1998),
the mechanism behind this phenomenon is not understood. As
viral infection can directly induce dendritic cells to stimulate
CTL, some antiviral responses could depend more on T helper
cells than others. Although not experimentally proven, there
may be a correlation between the helper independence of a
virus-specific CTL response and the ability of a virus to both
infect and condition dendritic cells.
In this review, we have focussed mainly on the role of
dendritic cells in the pathogenesis of two human viral diseases :
measles as an example of an acute, self-limiting infection, and
AIDS, as an example of a chronic persistent infection. Both
infections are characterized by the disruption of immune
functions. In both systems, it appears that only small amounts
of virus are needed for infection, that virus production from
infected dendritic cells is low but can be enhanced after
coculture with activated or memory T cells, and that infected
dendritic cells largely fail to stimulate T cells. Once acquired by
dendritic cells, viral antigens may be processed and presented
in a conventional way within the draining lymph nodes to
produce immune responses. Both for HIV and MV, dendritic
cells may also serve as an efficient means of transport and
spread of the virus during the acute phase of infection.
Dendritic cells will carry live virus into the lymph nodes and
ultimately to T cells. In addition, MV-infected dendritic cells
may play a central role in the establishment of a pronounced
suppression of T cell functions. This suppression, however, is
only transient since MV causes a highly cytolytic and not a
persistent infection of dendritic cells. In contrast, dendritic cells
can become persistently infected with viruses such as HIV and
serve as reservoirs for viruses during chronic infections. In HIV
infection, dendritic cells may carry a long-term infection and
produce virus only as they mature. Thus, they may act as a
continuing source of infected cells in further cycles of nonproductive and then productive infection. Other viruses may
use this strategy, too. It has, for instance, been found that
cytomegalovirus is carried within a small percentage of
myeloid and dendritic cell progenitors in the healthy seropositive host and virus reactivation may be triggered by
factors associated with the inflammatory response (Hahn et al.,
1998).
The role of virus-related changes in the function of bone
marrow-derived dendritic cells, in relation to the pathogenesis
of AIDS and measles, has been outlined in this review. There
may, of course, be additional ways in which viruses might
interfere with dendritic cell function. For instance, it has been
shown that type I IFN, which is produced during many viral
infections, prevents the release of IFN-γ and TNF-α from CD4+
T cells. These cells, instead, produce large amounts of IL-10. In
turn, IL-10 and the low level of IFN-γ production interfere with
the maturation and release of IL-12 from dendritic cells (Morel
et al., 1997). When applied directly to dendritic cells (in the
absence of T cells), type I IFN, by itself, prevents IL-12 release
from dendritic cells. Thus, type I IFN inhibits both IL-12dependent and -independent Th1 cytokine production and
provides a mechanism for the inhibition of IL-12-mediated
immunity in viral infection (McRae et al., 1998). In summary, a
detailed understanding of the interaction of viruses with cells
of the dendritic cell lineage is an essential component in our
comprehension of both the activation of virus-specific immune
reactions and the pathogenesis of viral disease.
We thank Stefan Niewiesk, Stella C. Knight and Volker ter Meulen for
helpful comments and the Deutsche Forschungsgemeinschaft, the
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ICJ
I. M. Klagge and S. Schneider-Schaulies
Bundesministerium fu$ r Bildung und Forschung, the Robert PflegerStiftung and the WHO for financial support.
infected dendritic cells results in generalized immunosuppression. Journal
of Virology 69, 1059–1070.
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