Institute for Virology and Immunobiology, University of Würzburg, Versbacher Str. 7, D-97078 Würzburg, Germany1
Miltenyi Biotech GmbH, 51429 Bergisch-Gladbach, Germany2
Emory University, Yerkes Vaccine Center, 954 Gatewood Road, Atlanta, GA 30322, USA3
The Second Department of Internal Medicine, School of Medicine, Mie University, 2-174 Edobashi, Tsu-City, Mie, Japan4
Author for correspondence: Sibylle Schneider-Schaulies. Fax +49 931 201 3934. e-mail s-s-s{at}vim.uni-wuerzburg.de
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Abstract |
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Introduction |
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Dendritic cells (DC) are professional antigen-presenting cells which are also located in the pulmonary airways, pulmonary vessels, alveolar septa and pleura, where they may function as sentinels for invading pathogens. After challenge with stimuli such as bacteria or soluble antigen, DC traffic from the lung to the draining LN where they are able to initiate primary immune responses (Banchereau & Steinman, 1998 ). It is also evident that targeting DC and interfering with DC maturation and function is a powerful strategy employed by pathogens to avoid immune recognition and to induce immunosuppression (Klagge & Schneider-Schaulies, 1999
; Knight & Patterson, 1997
). Mainly through the use of vaccine strains, DC were shown to be susceptible to MV infection (Fugier-Vivier et al., 1997
; Grosjean et al., 1997
; Klagge et al., 2000
; Schnorr et al., 1997
; Steineur et al., 1998
), although infectious particles were released at only low levels. The interaction of MV-infected DC with T cells enhances virus replication and syncytia formation in a CD40 ligation-dependent manner (Fugier-Vivier et al., 1997
; Servet-Delprat et al., 2000b
). Interestingly, a lymphotropic MV wild-type strain, WTF, was found to replicate very efficiently in DC cultures (Schnorr et al., 1997
). These observations suggest that DC infected with MV in the respiratory tract may transfer to the draining LN, where massive virus replication occurs, and that MV-infected DC may play a role in MV-induced immunosuppression.
Monkey kidney cell lines had been commonly used to isolate MV from peripheral blood lymphocytes or respiratory secretions until rapid and reproducible isolation of the virus from clinical specimens was reported using an EpsteinBarr virus (EBV)-transformed marmoset B-lymphocyte line, B95-8, and its derivatives. Importantly, isolates obtained by passage in one of the derivative lines, B95a, retained pathogenicity for monkeys, whereas MV adapted to Vero cells lost pathogenic potential (Kobune et al., 1990 ). Lymphotropic wild-type strains of MV and tissue culture-adapted MV vaccine strains possess different cell tropisms since lymphotropic strains grow poorly in adherent cells such as HeLa and Vero cells. To study the role of the viral glycoproteins in MV tropism, we generated recombinant vaccine MV based on the Edmonston-tag (ED-tag) molecular clone that contains one or both of the haemagglutinin (H) and fusion (F) proteins from a lymphotropic wild-type strain (WTF) (Johnston et al., 1999
). These viruses were viable and grew similarly in a lymphocytic cell line, whereas recombinant viruses expressing the WTF H protein showed a restricted spread in HeLa cells but not in Vero cells.
Using these recombinant viruses and the parental strain WTF to infect cotton rats, we found that the ability to replicate in secondary lymphoid tissues and to cause immunosuppression was restricted to viruses expressing the WTF H protein. Assuming that this could reflect differential interactions of these viruses with particular subpopulations of peripheral blood mononuclear cells (PBMC), we comparatively analysed infection of these recombinant MVs in monocyte-derived dendritic cells (Mo-DC) and in human peripheral blood lymphocytes (PBL). In PBL, recombinant MV containing ED H replicated more efficiently than WTF or recombinant viruses containing the WTF H protein. In Mo-DC, on the other hand, replication of recombinant MV containing ED H was restricted, but WTF and recombinant MV containing WTF H replicated well. This was associated with enhanced virus spread and accumulation of viral antigens as well as an enhancement of cellular fusion in these cultures.
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Methods |
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Preparation of PBL and generation of Mo-DC.
Human PBMC were isolated by FicollPaque density gradient centrifugation (Amersham Pharmacia) of buffy coats and cultured in RPMI 164010% FCS overnight. When indicated, the non-adherent fraction (PBL) was stimulated with phytohaemagglutinin (PHA, 2·5 µg/ml). For generation of Mo-DC, CD14+ monocytes were enriched from PBMC preparations by depletion of T cells by rosetting with AET-treated sheep red blood cells and subsequent removal of B and NK cells using anti-CD19- and anti-CD56-coated magnetic beads (Milteny Biotech). The plastic-adherent fraction of the monocyte-enriched cell population (more than 90% purity) was used to generate Mo-DC in vitro by culture in the presence of 50 ng/ml recombinant human GM-CSF (Novartis) and 30 ng/ml recombinant human IL-4 (Strathmann Biotech) for 7 days with fresh cytokines added on day 4.
Antibodies and FACS analysis.
The MV H-specific monoclonal antibody (MAb) (L77), the anti-MV-N MAb (F227), the anti-CD46 MAb (11/88) (Schneider-Schaulies et al., 1995 ) and the anti-signalling lymphocytic activation molecule (SLAM)/CD150 MAb (5C6) (Erlenhöfer et al., 2001
) were produced and purified in our laboratory. The vesicular stomatitis virus (VSV)-G protein-specific MAb was generously provided by Matthias Schnell, Pittsburgh, PA, USA. For intracellular stainings, cells were fixed with 3·7% paraformaldehyde and permeabilized with 0·33% saponin (ICN). Cell stainings were measured using a FACScan (Becton Dickinson) and the LysisII program and analysed with CELL QUEST software.
Virus binding and uptake.
For binding studies, virus preparations or, for control, preparations of mock-infected cells (Vero cells or BJAB cell, respectively) or culture medium were used. The amounts of viral glycoproteins in the virus preparations were adjusted by Western blot using antisera against the cytoplasmic domains of H and F proteins. The amounts of mock preparations added to the controls were adjusted to those used for the individual virus preparations. For analysis of virus binding, cells were incubated with viruses (or mock preparations) on ice for 1 h, washed twice with PBS containing 0·4% bovine serum albumin (BSA)0·02 % sodium azide, and stained with a MAb against MV H protein (L77), followed by a fluorescein isothiocyanate (FITC)-labelled goat anti-mouse IgG. For virus uptake studies, Mo-DC were incubated with viruses at an m.o.i. of 2·5 TCID50 per cell at 37 °C for 2 h followed by a 5 min wash with 0·14 M NaCl8 mM glycine pH 2·50·1% BSA and two subsequent washing steps. Cells were stained for FACScan analysis after 14 h cultivation in medium containing 100 µg/ml Z-fFG (Sigma) using the anti-MV-N MAb (F227) and FITC-labelled goat anti-mouse IgG.
Virus infection and fusion inhibition.
Cells were infected at an m.o.i. of 0·05 TCID50 per cell for 1 h at 37 °C, washed twice with RPMI 1640 and plated at a density of 105 cells per well in 1 ml medium. When indicated, 2·5 µg/ml PHA was added to PBL. Mo-DC were cultured in the cytokine-containing medium. For fusion inhibition studies, infected Mo-DC were plated at a density of 4x104 cells per well in 100 µl of RPMI 164010% FCS and cytokines (GM-CSF/IL-4) in the presence of antibodies (final concentration, 25 µg/ml). For determination of virus titres, samples (containing both supernatant and cells) were freezethawed and assayed by TCID50 titration on B95a cells.
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Results |
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Interaction of MV recombinants and WTF with human PBL and Mo-DC
The different ability of viruses containing the WTF H or ED H protein to replicate in secondary lymphatic tissues and to cause proliferative inhibition in vivo (Fig. 1) might reflect a differential interaction of these viruses with subpopulations of PBMC. Thus, human PBL (stimulated with PHA following infection) and immature Mo-DC were infected with the MV wild-type strain WTF, molecular cloned vaccine MV ED-tag or the ED-tag-based recombinant viruses MV(WTF F)ED, MV(WTF H)ED or MV(WTF F/WTF H)ED (Fig. 1A
) at an m.o.i. of 0·05 TCID50 per cell. In PBL, within 2 days of infection only viruses containing the ED H protein, ED-tag and MV(WTF F)ED, induced syncytia (Fig. 2A
, panels b and c), whereas only formation of cell clusters, not syncytia, was observed with WTF, MV(WTF H)ED and MV(WTF F/WTF H)ED (Fig. 2A
, panels d to f). With the latter viruses, small syncytia developed on day 3 post-infection (p.i.), which increased in number and size on day 4 (not shown). In contrast, extensive syncytium formation was observed in DC infected with viruses containing the WTF H protein [WTF, MV(WTF H)ED and MV(WTF F/WTF H)ED] within 2 days p.i. (Fig. 2
, panels d to f), whereas syncytium formation was barely induced by viruses containing the ED H protein [ED-tag and MV(WTF F)ED] (Fig. 2
, panels b and c). These data indicate that the MV H protein has a strong impact on MV tropism for subpopulations of human PBMC.
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Discussion |
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The differential binding of ED H- and WTF H-containing viruses to unstimulated PBL probably represents their affinity for the constitutively expressed CD46, which is high for ED H and low for H proteins of most wild-type viruses propagated on PBMC, B95-8 or BJAB cells, including WTF (Bartz et al., 1998 ; Lecouturier et al., 1996
; Manchester et al., 2000
). A tyrosine residue at position 481 confers high, and asparagine confers low, affinity binding of MV H proteins to PBMC, which is in agreement with our observations that viruses containing the ED H protein (481Y) do interact with CD46-positive cells more efficiently than those containing WTF H (481N) (Johnston et al., 1999
) (Fig. 3
). Upon stimulation, the surface expression levels of CD150 increased as expected (not shown), which could explain the enhanced binding of both ED H- and WTF H-containing viruses (Fig. 3
). Since for the infection experiments (Fig. 5A
to C
), PBL were only stimulated with PHA after infection, viruses with higher affinity for CD46 are predominantly taken up and amplified rather than those mainly interacting with SLAM. Upregulation of this molecule after PHA stimulation may account for spread of and fusion by WTF H-containing viruses that occurred later than that with ED H protein-containing viruses in PBL (Fig. 5A
to C
).
On Mo-DC, both CD46 and SLAM were constitutively expressed (Fig. 4A). SLAM in particular was, however, detected only at low levels with 5C6, and barely with a commercially available anti-SLAM antibody (A12, Pharmingen) (Fig. 4A
and not shown). Since our Mo-DC were generated from CD14+ monocytes which were reported to be SLAM-negative (Cocks et al., 1995
; Sidorenko & Clark, 1993
), it would be interesting to determine when and by what mechanisms during DC maturation from these precursors this molecule is upregulated and how this correlates with susceptibility to infection with MV. Our finding that MV H proteins are important determinants for the differential tropism of MV strains for DC is in agreement with a recent study in which a single amino acid exchange within glycoprotein 1 conferred both DC tropism and immunosuppressive activity to lymphocytic choriomeningitis virus (LCMV; Sevilla et al., 2000
). Similar to our findings with PBL and ED H-containing viruses, a clear correlation was found in this study between the binding affinity of the immunosuppressive LCMV strains and their receptor,
-dystroglycan. It is unclear why, in contrast to PBL, we did not detect differential binding of MV containing ED H or WTF H proteins to DC (Fig. 3C
). Due to the low expression levels of SLAM, but also CD46 (Fig. 4A
), binding sites for all MV strains may not be very abundant and thus bound particles might not be detected. Specific binding to the less abundant SLAM in particular may additionally be masked by nonspecific binding of the MV H proteins to C-type lectin receptors such as mannose receptors, which are abundant on DC (Banchereau & Steinman, 1998
; Sallusto & Lanzavecchia, 1995
). Since formation of syncytia does occur in DC cultures infected with WTF H-containing viruses and this is efficiently prevented by anti-SLAM antibodies, it is clear that this molecule is expressed on DC and is functional in providing at least fusion helper function for lymphotropic MV strains (Fig. 4B
).
Although WTF H protein was found to determine the tropism for DC to a large extent by improving membrane fusion, virus uptake and spread, replication of the authentic parental WTF strain was more efficient in DC, indicating that other MV components may also be important (Fig. 5F). At present, the MV gene products involved and the underlying mechanisms are unclear. Experimental evidence has been provided that amino acid exchanges within the P gene relate to MV attenuation and to replication efficiencies in lymphoid cells in vitro and in vivo (Takeda et al., 1998
; Takeuchi et al., 2000
). Moreover, disruption of the C reading frame, which is also encoded within the P gene, was associated with attenuation of MV replication in PBMC (Escoffier et al., 1999
), and both C and V proteins were found to determine MV virulence after intracerebral infection of mice (Patterson et al., 2000
). It is currently unknown by which mechanisms these proteins may affect MV replication in lymphoid cells. C and/or V proteins were linked to modulation of either induction or action of type I IFN in related virus systems (Goodbourne et al., 2000
). Differential induction of type I IFN as suggested by a recent study for MV wild-type strains (Naniche et al., 2000
) is, however, not likely to play a role in our system, since both the MV Edmonston strain B (which is the parental strain of the molecular clone ED-tag) and the WTF strain induce type I IFN after infection of DC cultures to similar levels (Klagge et al., 2000
; I. M. Klagge, unpublished). Induction of type I IFN as a result of CD46 ligation as described in mouse macrophages (Katayama et al., 2000
) is also unlikely to be important in our system, since at least in PBL ED H protein-containing viruses strongly interacting with CD46 replicated well (Fig. 5A
to C
). In addition, expression levels of CD46 on DC are much lower (Fig. 4A
), and firm binding to DC was not observed with either virus strain (Fig. 3C
). If WTF were able to evade type I IFN efficiently by whatever mechanism, it would be difficult to explain why it should fail to do so in PHA-stimulated PBL (Fig. 5C
). Implying that the antiviral activity of type I IFN can be cell type-specific, we have documented that MxA protein does not interfere with MV replication in Vero cells, but inhibits virus transcription in neural cells and accumulation of MV glycoproteins in a monocytic cell line (Schneider-Schaulies et al., 1994
; Schnorr et al., 1993
). Since WTF readily replicates on DC, at least MxA-mediated restrictions obviously do not occur in these cells (Fig. 5D
).
Importantly, the tropism of WTF H-containing viruses in vitro correlated both with their enhanced spread to mediastinal LN in vivo and with the induction of immunosuppression indicated by impaired proliferative responses of lymphocytes to mitogen stimulation ex vivo (Fig. 1C). Whether a SLAM orthologue is expressed in these animals is not known as yet. It is of interest to note that the source of the F protein did not influence either the tropism of the recombinant viruses for PBL or DC in vitro or the virus spread to the LN and the induction of immunosuppression in vivo. Based on our observations made in vitro, these findings suggest that expression of H proteins of lymphotropic MV strains may facilitate entry of these viruses into DC also in vivo. As indicated by our findings with WTF (Fig. 5E
), as yet unknown virus determinants allow these viruses to replicate efficiently in DC. Ongoing virus replication of particularly MV WTF in immature DC was associated with a more rapid maturation of these cells (Schnorr et al., 1997
) which can thereby be recruited more quickly into secondary lymphatic tissues. By processing and presenting MV antigens, MV infected DC may initially stimulate a primary antiviral immune response, but also efficiently transmit infectious virus to uninfected DC. Moreover, virus replication may be additionally stimulated by CD40 ligation (Servet-Delprat et al., 2000b
). MV-infected DC are likely to undergo rapid cell death either by fusion or by apoptosis (Fugier-Vivier et al., 1997
; Grosjean et al., 1997
; Servet-Delprat et al., 2000a
). In agreement with previous findings (Fugier-Vivier et al., 1997
), transmission of virus from DC to T cells occurred only to a very limited extent irrespective of the recombinant MV strain used (not shown). Inhibition of T cell proliferation may, however, have been largely brought about by the MV F/H proteins which accumulate to high levels at the surface of DC infected with WTF H-containing viruses (Fig. 5E
; Schnorr et al., 1997
), and which were previously found to confer T cell unresponsiveness in a contact-dependent manner both in vitro and in vivo (Klagge et al., 2000
; Niewiesk et al., 1997
; Schlender et al., 1996
). Thus, MV H proteins allowing specific targeting of DC are likely to enhance the immunosuppressive activity of their corresponding viruses by a faster and more efficient transport of virus into secondary lymphoid tissues.
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Acknowledgments |
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References |
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Received 19 March 2001;
accepted 11 April 2001.