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Journal of General Virology (1999), 80, 823–833. Printed in Great Britain ................................................................................................................................................................................................................................................................................... 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 0001-6125 # 1999 SGM Downloaded from www.microbiologyresearch.org by IP: 88.99.165.207 On: Fri, 12 May 2017 04:25:35 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 Downloaded from www.microbiologyresearch.org by IP: 88.99.165.207 On: Fri, 12 May 2017 04:25:35 Review : Viruses and dendritic cells 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 Downloaded from www.microbiologyresearch.org by IP: 88.99.165.207 On: Fri, 12 May 2017 04:25:35 ICF 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 Downloaded from www.microbiologyresearch.org by IP: 88.99.165.207 On: Fri, 12 May 2017 04:25:35 Review : Viruses and dendritic cells 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 Downloaded from www.microbiologyresearch.org by IP: 88.99.165.207 On: Fri, 12 May 2017 04:25:35 ICH 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 Downloaded from www.microbiologyresearch.org by IP: 88.99.165.207 On: Fri, 12 May 2017 04:25:35 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). 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