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Journal of Virology, March 1999, p. 2212-2221, Vol. 73, No. 3
Laboratoire d'Immunobiologie Fondamentale et
Clinique,
Received 3 August 1998/Accepted 7 December 1998
Measles virus infection induces a profound immunosuppression that
may lead to serious secondary infections and mortality. In this report,
we show that the human cortical thymic epithelial cell line is highly
susceptible to measles virus infection in vitro, resulting in
infectious viral particle production and syncytium formation. Measles
virus inhibits thymic epithelial cell growth and induces an arrest in
the G0/G1 phases of the cell cycle. Moreover, we show that measles virus induces a progressive thymic epithelial cell
differentiation process: attached measles virus-infected epithelial
cells correspond to an intermediate state of differentiation while
floating cells, recovered from cell culture supernatants, are fully
differentiated. Measles virus-induced thymic epithelial cell
differentiation is characterized by morphological and phenotypic changes. Measles virus-infected attached cells present fusiform and
stellate shapes followed by a loss of cell-cell contacts and a shift
from low- to high-molecular-weight keratin expression. Measles virus
infection induces thymic epithelial cell apoptosis in terminally
differentiated cells, revealed by the condensation and degradation of
DNA in measles virus-infected floating thymic epithelial cells. Because
thymic epithelial cells are required for the generation of
immunocompetent T lymphocytes, our results suggest that measles
virus-induced terminal differentiation of thymic epithelial cells may
contribute to immunosuppression, particularly in children, in whom the
thymic microenvironment is of critical importance for the development
and maturation of a functional immune system.
The primary causes of infant
death in developing countries are associated with measles virus (MV)
and human immunodeficiency virus (HIV) infection. Both infections
result in the development of profound immunosuppression that
contributes to secondary infections and mortality (4, 11, 18,
27). The dysfunction of the immune system in HIV patients is
dramatic and ultimately fatal, whereas MV-induced immunosuppression is
transitory. The physiological mechanisms involved in MV-induced
immunodepression are still not well understood. The first indication of
MV-induced immunosuppression is a transient unresponsiveness to
tuberculin that is observed for several weeks after recovery from MV
infection (47). Furthermore, in vitro stimulation of
lymphocytes by mitogens (26, 35) or alloantigens
(15) is suppressed after MV infection, and cytokine production has been shown to be abnormal as well (14, 22, 39,
48). Suppression of antibody synthesis as well as natural killer
cell activity was reported in different in vitro and in vivo models
(7, 19, 43, 50). Infection of dendritic cells with MV leads
to a rapid up-regulation of activation markers, indicating their
functional maturation in vitro (39). As a result, MV-infected dendritic cells suppressed mitogen-dependent proliferation of uninfected peripheral blood lymphocytes or T cells (14, 20, 39). Finally, it has been demonstrated that MV could induce apoptosis of infected cells and noninfected lymphocytes
after their contact with infected cells in vitro (1, 9,
14).
Measles virus, belonging to the Paramyxoviridae family and
the Morbillivirus genus, is an enveloped nonsegmented-strand
RNA virus. Infection with MV is initiated by interaction of viral hemagglutinin (H) protein with the cellular receptor, the CD46 molecule, initially described as the membrane cofactor protein (8,
16, 30). This attachment is followed by virus-cell fusion,
release of nucleocapsids into the cytoplasm, and expression of H and
fusion (F) glycoproteins at the cell surface. During infection, CD46 is
down-regulated concomitantly with the appearance of MV H protein on the
cell surface (24, 30, 37). MV initially replicates in the
respiratory tract and then spreads to local lymphoid tissue, where
virus replication can occur in macrophages and/or in dendritic cells
(10, 14, 20). This secondary viremia allows the spreading of
the virus to other lymphoid organs, such as the thymus, liver, skin,
and conjunctive tissues (6, 29, 49). Thymic stromal cells
have been described as a target for MV in the SCID-hu mouse model after
direct intrathymic inoculation of MV. As a result, MV replication in
the thymic epithelial cells (TEC) as well as monocytes/macrophages
leads to induction of thymocyte apoptosis (3, 45).
Similarly, TEC were shown to be prominent targets of HIV and human
cytomegalovirus infection, where infection of thymic epithelium is
associated with profound thymic injury (2, 5, 28, 40, 41).
TEC play a critical role in the development and maturation of
immunocompetent T cells, providing a microenvironment with a unique
capacity to generate a functional and diverse T-cell repertoire (21). Thus, the interaction of virus with the thymic
microenvironment may result in an alteration in the development of
functional T cells. In this study, we demonstrate that MV infection
induces terminal differentiation of TEC which is characterized by the arrest of proliferation and by morphological and phenotypic changes typical of epithelial cell maturation, followed by apoptosis of fully
differentiated TEC. These results suggest that MV-induced terminal
differentiation of TEC may contribute to a long-term immune
dysfunction, particularly in infants, in whom ontogenesis of the immune
system requires a functional thymic microenvironment.
Cell culture, MV infection, and viral titration.
The
previously described (12) P1.4D6 cortical TEC clone from
human postnatal thymus was used. TEC were cultured in RPMI 1640 (Gibco
Life Technologies, Inc., Grand Island, N.Y.) supplemented with 2 mM
L-glutamine (Gibco Life Technologies), 10 mM HEPES (Gibco Life Technologies), 40 µg of gentamicin (Schering-Plough)/ml, and
10% fetal calf serum (Gibco Life Technologies). TEC were subcultivated at low density before infection, and attached TEC (3 × 103 cells/cm2 in 25 ml of culture medium) were
infected with 1 PFU/cell of Vero-cell-derived infectious MV Hallé
strain over a 2-h period, followed by three extensive washes. (These
cells will be referred to hereafter as MV-TEC.) As a control, medium or
MV inactivated by UV light over 30 min at 254 nm (UV-MV-TEC) was used.
This MV strain has been classified as the vaccine MV Edmonston-like
strain (34). Production of infectious MV particles from
cell-free supernatant cultures was measured at different time points
after infection on a highly permissive Vero cell monolayer where
infectious-MV particles had formed lytic plaques. Less than 24 h
before each experiment, cell supernatants from MV-TEC were removed.
Attached TEC were collected after treatment with 1 mM EDTA.
Cytofluorometry analysis.
The monoclonal antibodies (MAbs)
used were clone MCI20.6 (CD46; immunoglobulin G1 [IgG1] isotype
[31]), clone 55 (anti-H; IgG2b isotype
[17]), clone 120 (anti-nucleoprotein [NP]; IgG2b isotype [17]), clone Y503 (anti-F) (kindly provided by
F. Wild [Lyon, France]), CAM5.2 (IgG2b isotype [Becton Dickinson,
Mountain View, Calif.]), and AE3 (IgG1 isotype [Diagnostic
Biosystems, Fremont, Calif.]). These latter two MAbs recognize keratin
polypeptides of low (43 and 50 kDa) and high (58 and 65 to 67 kDa)
molecular masses, respectively. Mouse IgG1 and IgG2b isotypic controls
(Immunotech, Marseille, France) were used as negative controls of immunofluorescence.
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Measles Virus Infection Induces Terminal
Differentiation of Human Thymic Epithelial Cells
ABSTRACT
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
m), 5 × 105 cells were incubated
with 3,3'-dihexyloxacarbocyanine [DIOC6(3)], a
fluorescent dye (40 nM in phosphate-buffered saline; Molecular Probe,
Inc., Eugene, Oreg.), for 15 min at 37°C before analysis. During
apoptosis, an increase of fluorescence may first be observed, resulting
in an increase in mitochondrial volume (m)
(46) and followed by a decrease of DIOC6(3)
fluorescence, thus characterizing apoptosis (51).
Cells were analyzed with a FACScan flow cytometer (Becton Dickinson;
Cellquest software). Integrated fluorescence was measured, and data was
collected from at least 10,000 events.
Indirect immunofluorescence staining. Cytospin preparations of 7 × 104 attached TEC were fixed in acetone for 10 min at 4°C. Briefly, immunofluorescence staining was performed by using a mouse anti-cytokeratin CAM5.2 or AE3 MAb. These MAbs were revealed with FITC-conjugated anti-mouse Ig. The cells were observed with a Zeiss microscope (Carl Zeiss Inc., Thornwood, N.Y.).
DNA fragmentation analysis. DNA laddering was performed as described previously (23). Briefly, TEC monolayers (directly lysed in the flask) and floating MV-TEC were lysed at different time points after infection, with 0.5% Triton X-100, 5 mM Tris (pH 7.5), 20 mM EDTA, and 0.1 mg of proteinase K (Boehringer)/ml for 20 min on ice. The low-molecular-weight DNA was isolated by centrifugation at 13,000 × g for 10 min, extracted twice with phenol/chloroform, precipitated by ethanol, and resuspended in 10 mM Tris-1 mM EDTA (pH 8) containing 100 µg of RNase A/ml over a 2-h period at 37°C. DNA from attached (50 µg) and from floating (2.5 µg) TEC were separated by electrophoresis for 3 h on a 1.5% agarose gel in Tris-borate-EDTA buffer and visualized by staining with 0.1 µg of ethidium bromide (Boehringer Mannheim)/ml. The molecular weight standards were based on multiples of a 200-bp DNA ladder (Eurogentec).
Evaluation of cell death. Nuclear morphology of TEC monolayers on Lab-Tek chamber slides (Miles Laboratories, Naperville, Ill.) or floating cells from supernatants was examined after staining with 10 µg of Hoechst 33342 (Sigma)/ml for 30 min at 37°C. After fixation with 1% formol, the cells were observed with a Zeiss microscope (Carl Zeiss Inc.). Nuclear fragmentation and marked condensation of the chromatin with reduction of nuclear size defined apoptotic cells.
Electron microscopy. Pelleted cells were fixed for 1 h in 0.1 M sodium cacodylate buffer containing 1% glutaraldehyde and 0.5% paraformaldehyde (final concentration). Postfixation was done in the same buffer containing 1% osmium tetroxide. The fixed and dehydrated pellets were embedded in Epon resin. Ultrathin sections were successively stained with methanolic uranyl acetate and lead citrate. Electron micrographs were taken with a Philips CM 120 electron microscope at the Electron Microscopy Center of the University of Lyon.
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RESULTS |
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Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
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TEC are susceptible to MV infection in vitro. The ability of human TEC to produce infectious viral particles was measured by assaying the culture supernatant for PFU at different time points after infection (Fig. 1). MV infection of TEC was productive and reached a peak at day 5 postinfection (4.09 ± 0.04 log10 PFU/ml) (Fig. 1A) with syncytium formation in less than 10% of infected TEC layers (see Fig. 5B and data not shown). In contrast, no MV production or syncytium formation was detected in cultures of TEC exposed to UV-inactivated MV (see Fig. 5B).
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Impaired growth of MV-TEC. The consequence of MV replication on TEC growth was then analyzed by evaluating the number of viable cells by trypan blue exclusion (Fig. 2). The number of viable MV-TEC was lower than those of UV-MV-TEC and uninfected TEC, suggesting that arrest of cell growth and/or cell death occurred in MV-TEC (Fig. 2A). The absence of thymidine incorporation from the MV-TEC cultures indicated that a cell growth arrest occurred (data not shown).
We next analyzed the cell cycle distribution of infected and uninfected TEC at different time intervals from 1 to 7 days postinfection. Our results demonstrated a significant decrease of MV-TEC in the S/G2/M phases of the cell cycle from 50.1% ± 1.8% by day 1 to 21.8% ± 4% by day 7 and subsequently an accumulation in the G0/G1 phases of the cell cycle (Fig. 2B). Cell cycle arrest in the G0/G1 phases was linked to the replication of MV in TEC, since cell cycle distribution did not change during the culture of uninfected cells (data not shown) and UV-MV-TEC (remaining at between 44.9% ± 3.7% to 47.7% ± 4.4% in the S/G2/M phases) (Fig. 2B).MV replication induced TEC differentiation. UV-MV-TEC monolayers were highly packed and formed regular clones characteristic of typical epithelial cells in culture (Fig. 3A). Significant morphological differences in MV-TEC monolayers were observed (Fig. 3D). MV-TEC lost classical epithelial-like morphology, decreased cell-cell contacts, and acquired the squamous phenotype of highly differentiated TEC with fusiform to stellate shapes of dispersed single cells (Fig. 3D).
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MV-TEC died by apoptosis. Trypan blue staining indicated that all floating MV-TEC were dead (data not shown). In order to understand the mechanisms of cellular death induced by MV, DNA fragmentation in attached and floating cells was evaluated. A weak degradation of genomic DNA was observed in attached MV-TEC at days 3 to 7 (Fig. 5A). A typical internucleosomal fragmentation of DNA was observed in floating MV-TEC from days 3 to 7 postinfection (Fig. 5A). In contrast, no degradation in attached controls such as uninfected TEC (data not shown) and UV-MV-TEC (Fig. 5A) was detected. These data were confirmed and expanded by the study of the nuclear morphology in attached and floating MV-TEC by Hoechst 33342 staining. Less than 10% of attached MV-TEC showed nuclear fragmentation, and these apoptotic cells were found only in syncytia (Fig. 5B). In contrast, more than 90% of floating MV-TEC showed nuclear condensation characteristic of apoptosis (Fig. 5B).
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MV-induced mitochondrial swelling and hyperpolarization of attached
TEC.
To further investigate the initial steps of MV-TEC apoptosis,
we studied the early alterations of mitochondria by electron microscopy
analysis and DIOC6(3) staining, specific for the changes in
the m (Fig. 6).
Electron-microscopic observations revealed that uninfected and
UV-MV-TEC contained an irregularly shaped nucleus, large bundles of
cytoplasmic intermediate filaments, and numerous clustered mitochondria
(data not shown). In contrast, MV-TEC showed some swelling mitochondria
with an electron-dense matrix (Fig. 6B) or with a disruption of the
outer membrane (Fig. 6C). Some MV-TEC presented normal mitochondria
(Fig. 6A). The accumulation of DIOC6(3), measuring an
increase in m, was observed in attached MV-TEC by
flow cytometry at day 7 postinfection. A consistent decrease in the
m compared to controls was detected in floating
MV-TEC (Fig. 6D).
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DISCUSSION |
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Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
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Mechanisms of pathogen-induced cell differentiation, particularly in the thymic epithelium, are still largely unknown. We showed here that TEC are highly susceptible to MV infection in vitro, resulting in massive viral replication and syncytium formation. These data are in agreement with previous findings based on in vitro and in vivo analyses and suggest that the thymic epithelium may be a target for MV and may indirectly provoke thymic injury by causing thymocyte depletion (3, 6, 29, 33, 45, 49). However, the alteration in cell functions induced by MV replication was not determined in these studies. We used a human cell clone derived from cortical thymic epithelium (12) to analyze a direct effect of MV on this cell type, without the potential interference and/or interaction of other cell populations present in thymic organ cultures. The present study demonstrates for the first time that MV replication in thymic epithelial cells induces terminal cell differentiation followed by apoptosis.
Consequent to MV replication, the ability of TEC to proliferate was profoundly affected, with an arrest in the G0/G1 phases of the cell cycle. An induction of growth arrest by MV was previously shown in other cell types, and various mechanisms were proposed. MV-induced impairment of uninfected peripheral blood lymphocyte proliferation did not require viral replication but was dependent on the coexpression of MV H and F glycoproteins by the MV-infected and irradiated cells (36, 38). Our study indicates that viral replication is critical for the TEC growth arrest since UV-MV, containing H and F membrane proteins, does not have any effect. However, we do not exclude the role of H and F proteins in the inhibition of TEC proliferation. Under the conditions of our study, the amount of H and F expressed early in UV-MV-TEC may be insufficient to trigger differentiation signals. In addition to H and F viral proteins, the expression of other viral protein(s) may be required as well. The role of this protein(s) remains to be elucidated.
In addition to cell growth arrest, our study demonstrates that when replicating MV, cortical thymic epithelium undergoes major changes in morphology, associated with acquisition of fusiform and stellate cellular shapes, squamous morphology, and a loss of cell-cell contacts. These findings strongly suggest that MV replication in TEC induced cell differentiation. We confirmed this observation by performing immunostaining to analyze phenotypic changes characteristic of differentiated TEC. We demonstrated that MV promotes a shift from low- to high-molecular-weight keratin expression, characteristic of differentiated epithelial cells (13, 42). This MV-induced differentiation mechanism corresponds to a progressive process correlating with the impairment of TEC growth beginning at day 3 after infection. The down-regulation of low-molecular-weight keratin expression at day 5 is followed by the acquisition of high-molecular-weight keratin and by morphological changes at day 7, ending with a complete destruction of in vitro cortical thymic epithelium layers. This observation is in agreement with previous studies demonstrating that differentiated TEC contain specific cytoskeletal proteins which are associated with late stages of epidermal keratinocyte maturation (25). However, very little is known about the cortical TEC differentiation process in vitro and in vivo. Therefore, we may hypothesize that cortical and medullary TEC could share a common TEC differentiation pathway.
MV replication in cortical TEC is required to induce the differentiation process ending with apoptosis of fully differentiated TEC in vitro. Our observation is in agreement with other studies, in which autopsies of patients with fatal measles infections demonstrated lesions in the thymus with degenerative and/or necrotic changes associated to a rapid and predominant loss of the thymic cortex (49). A marked involution of the thymic medulla was also observed, and MV antigens were found in Hassall's corpuscles and in adjacent MV-infected thymic stromal cells (6, 29, 45, 49). We demonstrated that MV-induced apoptosis was seen in fully differentiated TEC but also in syncytia. The ability of MV to induce apoptosis has been observed in some cell lines (9), infected peripheral blood lymphocytes (1), and dendritic cells (14), as well as in T cells in contact with infected dendritic or epithelial cells (3, 14). Our data showing progressive mitochondrial swelling and disruption of the outer mitochondrial membrane indicate that differentiated MV-TEC are committed to apoptosis before they detach from matrix. These characteristics have been previously defined to be specific of early steps of apoptosis (46). In addition, late stages of apoptosis were detected in fully differentiated floating MV-TEC as well as in syncytia of attached MV-TEC. The characteristic of large syncytial multinucleated giant cells, the so-called Warthin-Finkeldey cells, resulting from fusion of more than 100 nuclei, have been described in lymphoid tissues, such as that of the thymus, during the early phase of measles (32). In addition to differentiation-induced apoptosis, it is possible that the cytopathic effect of MV leads also to apoptosis of syncytium-forming TEC.
In addition, MV replication in TEC leads to CD46 down-regulation. A correlation between CD46 internalization and in vitro susceptibility to complement-mediated lysis has been reported (37). Therefore, MV-induced CD46 down-regulation may render TEC susceptible to complement-mediated lysis, which could contribute to thymic damage observed during MV infection.
Recent reports have shown that in vivo MV infection of TEC leads to induction of thymocyte apoptosis, which may contribute to a long-term alteration of the immune system (3, 45). As thymocyte survival depends on the signal provided by stromal cells, it remains to be determined if the destruction of cortical thymic epithelium observed in vitro is induced directly, by MV replication, or indirectly, by complement-mediated lysis, and whether it could deliver abnormal signal to thymocytes and/or affects positive selection of thymocytes. As MV infection most often occurs in childhood, when the functioning of the thymus is required, defects in TEC function and survival may contribute to the immune dysfunction and to the development of immune suppression.
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ACKNOWLEDGMENTS |
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We particularly thank J.-F. Nicolas and J. Marvel for their scientific advice during this work. We are grateful to J. Maryanski and V. Lotteau for reading the manuscript and to S. Manier, D. Gerlier, and P. Jurdic for helpful suggestions. We also thank Y. Leverrier, A. Cheff, A. Thomas-Cachard, M.-T. Nugeyre, C. Domenget, and M. Chamoux for valuable technical assistance. The useful comments of C. Servet-Delprat, A. Astier, M.-C. Trescol-Biémont, S. Guerret, and P.-O. Vidalin are greatly appreciated.
This work was supported in part by institutional grants from the Centre National de la Recherche Scientifique, the Ministère de l'Education National, de l'Enseignement Supérieur et de la Recherche, l'Institut National de la Santé et de la Recherche Médicale and by additional support from Association pour la Recherche sur le Cancer (CRC 6108) and from the Programme de Recherche sur le Vieillissement de la Région Rhône-Alpes (97-98). A.E. is a recipient of a grant from the Fondation pour la Recherche Médicale.
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FOOTNOTES |
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* Corresponding author. Mailing address: Laboratoire d'Immunobiologie Fondamentale et Clinique, INSERM U503, ENS de Lyon, 46, Allée d'Italie, 69364 Lyon Cedex 07, France. Phone: (33) 4 72 72 80 13. Fax: (33) 4 72 72 86 69. E-mail: Helene.Valentin{at}ens-lyon.fr.
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Abstract
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Materials and methods
Results
Discussion
References
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Journal of Virology, March 1999, p. 2212-2221, Vol. 73, No. 3
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