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Published ahead of print on December 4, 2003, doi:10.1164/rccm.200305-663OC
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American Journal of Respiratory and Critical Care Medicine Vol 169. pp. 494-498, (2004)
© 2004 American Thoracic Society

Regulation of Mite Allergen-pulsed Murine Dendritic Cells by Respiratory Syncytial Virus

Yuki Kondo, Hiroto Matsuse, Ikuko Machida, Tetsuya Kawano, Sachiko Saeki, Shinya Tomari, Yasushi Obase, Chizu Fukushima and Shigeru Kohno

Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan

Correspondence and requests for reprints should be addressed to Hiroto Matsuse, M.D., Second Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852–8501, Japan. E-mail: hmatsuse{at}net.nagasaki-u.ac.jp


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Dendritic cells (DCs) are the only antigen-presenting cells that determine T-cell differentiation and play an important role in both allergy and viral infection. Respiratory syncytial virus (RSV) can infect DCs and affect their functions. The aim of this study was to determine the interaction between RSV infection and Dermatophagoides farinae allergen (D. farinae) sensitization on the development of allergy at the DC level. Murine bone marrow–derived DCs were prepared and treated as: control; D. farinae–pulsed DCs (D. farinae–DCs); ultraviolet-inactivated RSV challenged; RSV-infected, D. farinae–pulsed plus ultraviolet-inactivated RSV-challenged; and D. farinae–pulsed plus RSV-infected. In in vitro experiments, we compared the expression of costimulatory molecules and cytokine production between the six groups of DCs. Another group of naive mice were then intranasally inoculated with these DCs, after which intranasal challenge with D. farinae was performed to develop allergic airway inflammation in vivo. In comparison with D. farinae–DCs, D. farinae–pulsed plus RSV-infected DCs showed helper T cell (Th) 1–favored expression of costimulatory molecules and cytokine production. Allergic airway inflammation induced by intranasal instillation of D. farinae–DCs was abrogated when infected with RSV, which was associated with a concomitant suppression of Th2 response in the lung. Our results indicated that RSV suppresses D. farinae–DCs to induce Th2 response both in vitro and in vivo through regulation of expression of surface markers and production of immunoregulatory cytokines.

Key Words: Dermatophagoides farinae • animal model • cytokine • asthma

Previous studies have suggested a pathogenic link between asthma and respiratory viral infection (1, 2). Viral infections in early childhood prevent late development of allergic disease (hygiene hypothesis) (3), whereas respiratory viral infections are considered a risk factor for the development of asthma as well as mite allergen exposure (4–6). Respiratory syncytial virus (RSV) is a major pathogen of severe lower respiratory tract disease in infancy (7–9). Most infants infected with RSV are less than 2 years of age and tend to develop a bronchiolitic pattern of clinical features (10). Among many respiratory viruses, RSV has attracted special attention in the interaction with the development of asthma (8, 10).

The mouse is an excellent model for studying the interaction between RSV infection and allergen sensitization (11, 12). Several studies have shown that RSV infection in aeroallergen-sensitized mice exacerbates airway inflammation (13–15). On the other hand, RSV infection before allergic sensitization attenuates allergic airway inflammation (16). In addition, RSV infection during ovalbumin sensitization suppresses Th2 cytokine profile in lung tissues (17). Thus, the interaction between RSV infection and allergen sensitization remains to be determined.

Dendritic cells (DCs) play an important role in primary allergic sensitization to aeroallergens (18). DCs are involved in antigen uptake, processing, and presentation of antigenic fragments to T cells in the respiratory mucosa (19). DCs are the only antigen-presenting cells that can prime naive T cells and initiate primary T cell–mediated responses (20, 21). DCs also determine the development of T cell–mediated immune responses into either helper T cell (Th1) or Th2 (22, 23) and play a central role in initiating the adaptive immune response against infection (24). Furthermore, it is reported that respiratory viruses, such as RSV and measles, can infect DCs (25–27). Considered together, it seems that DCs play a major role in both allergy and viral infection. Although previous studies determined cytokine and chemokine production by RSV-infected immature DCs (26, 27), there are no reports that studied the effects of both RSV infection and allergen sensitization on DCs both in vitro and in vivo.

We hypothesized that DCs are key players in the interaction between RSV infection and mite allergen sensitization. To test this hypothesis, murine bone marrow–derived DCs were pulsed with mite allergen and/or infected with RSV in this study, and expression of costimulatory molecules and cytokine production was determined in vitro. Subsequently, these DCs were inoculated into the airway of naive mice, and their in vivo capacities to initiate allergic airway inflammation were compared. Our results indicated that RSV infection of mite allergen-pulsed DCs resulted in a shift of the immune response from Th2 to Th1 both in vitro and in vivo.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Virus
The human RSV A2 strain was purchased from the American Type Culture Collection (ATCC, Rockville, MD), and virus propagation was prepared by infection of Hep2 cells (ATCC) in a monolayer culture. An aliquot of the viral suspension was irradiated with ultraviolet (UV) light for 15 minutes on ice to inactivate the virus (UVRSV). Additional detail is provided in the online supplement.

Preparation of DCs
Six groups of murine bone marrow–derived DCs were prepared, including control DCs, Dermatophagoides farinae allergen (D. farinae)-pulsed DCs (D. farinae–DCs), UV-inactivated RSV-challenged DCs (UVRSV-DCs), RSV-infected DCs (RSV-DCs), D. farinae plus UVRSV-challenged DCs (D. farinae–UVRSV–DCs), and D. farinae plus RSV-infected DCs (D. farinae–RSV–DCs) from BALB/c mice, adapted from previous publications (28). At Day 9, a medium containing live RSV was inoculated into RSV-DCs and D. farinae–RSV–DCs. UV-inactivated RSV was inoculated into UVRSV-DCs and D. farinae–UVRSV–DCs. At Day 10, nonadherent cells were collected and washed. Cell pellets were pulsed with medium alone on control DCs, UVRSV-DCs, and RSV-DCs, whereas D. farinae–DCs, D. farinae–UVRSV–DCs, and D. farinae–RSV–DCs were pulsed with D. farinae allergens. At Day 11, the supernatants were subjected to cytokine (interleukin [IL]-10 and IL-12) assays. All experimental procedures were reviewed and approved by Nagasaki University School of Medicine Committee on Animal Research. Additional details are provided in the online supplement.

Flow Cytometric Analysis
The expressions of various surface markers on DCs were evaluated by staining the cells with fluorescein isothiocyanate–labeled antibodies to major histocompatibility complex (MHC) class II, CD40 and CD86 (all from BD PharMingen, San Diego, CA), and phycoerythrin-labeled antibody to CD11c (PharMingen). Data were presented as mean fluorescence intensity. Further details are provided in the online supplement.

In Vivo Priming with D. farinae–DCs
After 11 days of culture, the six groups of DCs were resuspended at 1 x 106 cells in 50-µl phosphate-buffered saline. They were inoculated intranasally into 4- to 5-week-old naive female BALB/c mice. Then all mice were challenged intranasally with 50 µg/50 µl of D. farinae for 5 consecutive days from Days 20 to 24.

Histopathologic Examination
Lung tissues harvested from the intranasally DC-inoculated mice were semiquantitatively analyzed as described previously (29). Additional details are provided in the online supplement.

Cytokine Assay of Mediastinal Lymph Nodes
Mononuclear cells were prepared from mediastinal lymph nodes of mice and cultured in the absence or presence of D. farinae. The concentrations of IFN-{gamma} and IL-5 in the supernatants were determined by ELISA. Additional details are provided in the online supplement.

Reverse Transcriptase-Polymerase Chain Reaction Analysis
Total RNA was isolated from DCs on Day 10 and lung tissues of intranasally DCs-inoculated mice. Murine toll-like receptor 4, ß-actin, and RSV N-protein–specific primers based on previous reports (30, 31) were used for reverse transcriptase–polymerase chain reaction. Additional details are provided in the online supplement.

Statistical Analysis
Results are expressed as mean ± SEM. Differences between groups were examined for statistical significance using repeated-measures analysis of variance with a Bonferroni multiple comparison test. A p value of less than 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
RSV Replicates in Murine Bone Marrow–derived DCs
The expression of murine toll-like receptor 4, which is important for activation of the innate immune response to RSV infection (32, 33), was confirmed in murine bone marrow–derived DCs by reverse transcriptase-polymerase chain reaction (Figure 1A) . In addition, virus replication was demonstrated in DCs 24 hours after infection with live RSV, whereas viral RNA could not be detected in UV-inactivated sham infected DCs (Figure 1A). The time-course study demonstrated that RSV RNA in DCs became detectable 24 hours after infection and disappeared 72 hours after infection (Figure 1B). Collectively, these results indicate that murine bone marrow–derived DCs express a receptor for innate immunity against RSV, and live RSV can replicate in DCs. In preliminary experiments, UV-inactivated or live RSV-infected DCs were intranasally inoculated into naive BALB/c mice. The expression of RSV N-protein mRNA in the lung tissues was determined by reverse transcriptase-polymerase chain reaction 4 days after intranasal transfer. In these RSV-infected DC-inoculated mice, no RSV replication was detected in lung tissues, whereas lung tissue obtained from live RSV-infected mice showed a positive signal (Figure 1C). Thus, any functional changes in mice intranasally inoculated with live RSV–infected DCs were due to these RSV-infected DCs rather than RSV per se.



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  		Figure 1. Analysis of toll-like receptor 4 (TLR-4) expression and respiratory syncytial virus (RSV) replication in murine bone marrow–derived dendritic cells (DCs) by reverse transcriptase-polymerase chain reaction. (A) The expression of murine TLR-4, ß-actin, and RSV N-protein mRNA in murine bone marrow–derived DCs was determined by reverse transcriptase–polymerase chain reaction. Lane 1, ultraviolet (UV)-inactivated RSV (UVRSV)–challenged DCs; lane 2, live RSV–infected DCs. (B) The expression of RSV N-protein mRNA in live RSV–infected DCs was determined by reverse transcriptase-polymerase chain reaction before (0 hours) and 4, 24, 48, 72, and 96 hours after infection. (C) BALB/c mice were intranasally inoculated with live RSV, UVRSV-challenged DCs, or live RSV–infected DCs. The expression of RSV mRNA was determined in lung tissues by reverse transcriptase-polymerase chain reaction, 4 days after the intranasal inoculation. Lane 1, live RSV; lane 2, UV-inactivated RSV–challenged DCs; and lane 3, live RSV–infected DCs.

 
RSV Infection Alters Expression of Surface Markers on D. farinae–DC
The percentage of CD11c+ and MHC II+ DCs was more than 90% with small contamination of B220+ B cells (approximately 7%) and CD68+ macrophages (approximately 3%) in all experimental groups. There were no significant differences among all groups with respect to the percentages and total viable cell numbers after D. farinae pulse and/or live RSV infection. The mean fluorescence intensity of surface markers (MHC class II, CD11c, CD40, and CD86) in the six groups of DCs is shown in Table 1 . In comparison with control DCs, the expression levels of MHC class II, CD11c, and CD86 were significantly higher, whereas that of CD40 was significantly lower in D. farinae–DCs, whereas live RSV infection of D. farinae–DCs significantly reversed these changes. UVRSV failed to show significant changes in both control and D. farinae–DCs. Live RSV infection alone significantly decreased the expression levels of MHC class II, CD11c, and CD86 and increased the expression of CD40 in DCs. Considered together, these results indicate that D. farinae pulse stimulates DC to produce a Th2 response, whereas live RSV infection shifts D. farinae–DCs to induce a Th1 response.


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  		TABLE 1. Expression of surface molecules on dendritic cells

 
RSV Alters Cytokine Response of D. farinae–DC
We also measured the concentrations of IL-10 and IL-12 in culture supernatants of the six groups of DCs (Figure 2) . UVRSV did not have any effect on the production of both cytokines. In comparison with control and RSV-DCs, D. farinae–DCs, D. farinae–UVRSV–DCs, and D. farinae–RSV–DCs produced significantly higher amounts of IL-10 and IL-12. Although the amounts of IL-12 production were comparable between D. farinae and D. farinae–RSV DCs, production of IL-10 was significantly lower in D. farinae–RSV DCs than in D. farinae–DCs. These results indicate that RSV infection shifts D. farinae–DCs to induce Th1-like cytokine response.



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  		Figure 2. Cytokine production by DCs. Concentrations of interleukin (IL)-12 and IL-10 in culture supernatants of DCs were determined by ELISA. Data represent mean ± SEM values of 12 experiments. *p < 0.01 versus control DCs; {dagger}p < 0.01 versus Dermatophagoides farinae allergen (D. farinae)–pulsed–DCs (D. farinae–DCs).

 
RSV Infection Attenuates D. farinae–DC–induced Allergic Airway Inflammation In Vivo
To determine whether the functional changes in DCs observed in vitro were actually translated in vivo, the six different groups of DCs were intranasally inoculated into naive mice, and then these mice were challenged intranasally with D. farinae. Representative photographs of lung pathology are shown in Figure 3I . Lung tissues of mice harboring RSV-DCs showed normal histology and were comparable with those seen in mice harboring the control DCs. In contrast, lung tissues of mice inoculated with D. farinae–DCs exhibited peribronchovascular cellular infiltration with lymphocytes and eosinophils. UVRSV did not show any significant pathologic effects on both control and D. farinae–DCs. In mice inoculated with D. farinae–RSV–DCs, D. farinae–DC–induced pulmonary inflammation was markedly attenuated. Semiquantitative analysis of lung pathology confirmed these changes (Figure 3II). These results indicate that RSV infection of D. farinae–DCs attenuated allergic airway inflammation.



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  		Figure 3. Histopathologic changes in the lungs of mice intranasally inoculated with DCs. (I) Lung tissues were obtained from mice intranasally inoculated with DCs and stained with hematoxylin and eosin. Representative microphotographs from each group are shown. (A) Mice inoculated with control DCs. (B) Mice inoculated with UVRSV-DCs. (C) Mice inoculated with RSV-DCs. (D) Mice inoculated with D. farinae–DCs. (E) Mice inoculated with D. farinae–UVRSV–DCs. (F) Mice inoculated with D. farinae–RSV–DCs, original magnification x400. (II) Histopathologic changes in the lungs were evaluated semiquantitatively. Results are expressed as mean ± SEM (n = 12 for each) number of eosinophils (Eo) and lymphocytes (Ly) in 10 peribronchovascular areas. *p < 0.01; §p < 0.05 vs. mice inoculated with control DCs; and {dagger}p < 0.01 vs. mice inoculated with D. farinae–DCs.

 
D. farinae–DCs Induce Th2-like Cytokines in Mediastinal Lymph Nodes, whereas RSV–D. farinae–DCs Induce Th1-like Cytokine Response
Finally, we compared the production of cytokines by mediastinal lymph node mononuclear cells in the six groups of mice (Figure 4) . UVRSV did not induce cytokine responses in control and D. farinae–DC–harboring mice. Both control and RSV-DC–harboring mice did not produce IL-5 and IFN-{gamma}. In contrast, isolated mononuclear cells from D. farinae–DC–inoculated mice produced significantly higher amounts of IL-5 and IFN-{gamma}. Production of both types of cytokines was significantly higher in D. farinae–RSV–DC–harboring mice compared with those harboring D. farinae–DCs. These changes were modest in IL-5 (approximately 1.7-fold), whereas they were marked in IFN-{gamma} (approximately fivefold). Thus, the protein ratio of IFN-{gamma} to IL-5 in D. farinae–RSV–DC–harboring mice was significantly higher than that of D. farinae–DC–harboring mice (13.8 ± 2.9 vs. 4.4 ± 1.3, p < 0.01). These results, together with those of in vitro experiments and lung pathology, indicated that RSV infection of D. farinae–DCs actually shifts the immune response from Th2 to Th1 in vivo.



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  		Figure 4. Cytokine profile in mediastinal lymph nodes of mice intranasally inoculated with DCs. Mononuclear cells from mediastinal lymph nodes were cultured in the presence of D. farinae allergen for 48 hours. The concentrations of IL-5 and IFN-{gamma} in culture supernatants were determined by ELISA. Bars represent mean ± SEM (n = 12 for each). *p < 0.01 vs. mice inoculated with control DCs; §p < 0.05; and {dagger}p < 0.01 vs. mice inoculated with D. farinae–DCs.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The immunologic link of DCs between respiratory viral infection and allergen sensitization in the development of allergy has been suggested. For example, influenza A virus infection prolonged the presence of DCs in the bronchial epithelium and augmented their capacities for antigen presentation (34). This study was designed to determine the interaction between D. farinae sensitization and RSV infection in DCs in vitro and then to examine the in vivo pathologic and immunologic effects of D. farinae-sensitized and RSV-infected DCs. For this purpose, murine bone marrow–derived DCs were pulsed with D. farinae and/or infected with RSV, and the expression of surface markers and production of immunomodulatory cytokines was compared. Subsequently, the airways of naive mice were inoculated with D. farinae–DCs and/or RSV-DCs, and lung pathology and cytokine profiles in mediastinal lymph nodes were examined. A critical limitation of this study is that RSV was inoculated into bone marrow–derived DCs; thus, some results might not reflect the actual effects of RSV infection on pulmonary DCs. To date, however, isolation of pulmonary DCs is still difficult, as these cells are rare in all body tissues, including lung, and isolation procedures are time consuming and cell yields are low (35).

Two parameters (surface markers and cytokines) were selected in this study to investigate the in vitro function of DCs. Surface markers expressed on DCs are important in naive T cell polarization. CD40 promotes Th1 polarization (36), whereas CD86 promotes Th2 polarization (37, 38). Bartz and colleagues (26) reported that RSV infection of immature DCs promoted DC maturation and increased the expression of MHC class II, CD80, CD86, CD83, and CD40. In this study, D. farinae reduced CD40 and increased CD86 expression in immature DCs, whereas RSV infection of D. farinae–pulsed mature DCs resulted in reversal of these expressions. Cytokine production from DCs was simultaneously measured, and IL-10 from D. farinae–DCs was significantly attenuated by RSV infection, which had no effect on IL-12 production. Previous studies indicated that IL-10 downregulates the production of IFN-{gamma} and IL-12 by CD4+ T cells and DCs (39). High amounts of IL-10 and low amounts of IL-12 induce naive CD4+ T cells to Th2 cells, whereas low amounts of IL-10 and high amounts of IL-12 induce Th1 cells (40). Collectively, our in vitro experiments demonstrate that RSV infection of D. farinae–DCs shifts the immune response from Th2 to Th1.

To determine whether in vitro RSV-induced functional changes in D. farinae–DCs also occur in vivo, we instilled these DCs into the airways of naive mice. Intranasal transfer of D. farinae–DCs followed by intranasal challenge with D. farinae caused allergic airway inflammation characterized by eosinophilic infiltration, which was associated with Th2 response in mediastinal lymph nodes. Allergic airway inflammation induced by transfer of D. farinae–DCs was ameliorated by RSV infection of DCs. In correlation with the functional change seen in DCs in vitro, assessment of the cytokine profile in mediastinal lymph nodes indicated that instillation of RSV-infected D. farinae–DCs resulted in IFN-{gamma} dominant Th1 response. Because UV-RSV failed to induce any effects in murine bone marrow–derived DCs, live replicable RSV seemed to be necessary to cause functional changes of DCs. However, similar to RSV infection of bovine DCs (41) and influenza virus infection of human DCs (42), little infectious virus was produced, as viral titers spread from transferred DCs in the airway of recipient mice were too low to show positive signal by reverse transcriptase-polymerase chain reaction. Taken together, these results indicated that these immunologic and pathologic responses were associated with functional changes of inoculated live RSV–infected DCs rather than with RSV infection per se.

Based on previous epidemiologic and experimental studies in humans and animals, it has long been suggested that RSV infection might be associated with the development and exacerbation of asthma (8, 43, 44). Experimental studies also showed that RSV infection could induce the production of larger amounts of IL-10 from immature DCs compared with influenza and parainfluenza viruses (26) and thus could potentially induce Th2 response. Based on these findings, we originally expected that RSV infection could enhance Th2 response in D. farinae–pulsed mature DCs. Unexpectedly, however, RSV infection inhibited D. farinae–DCs to induce Th2 responses both in vitro and in vivo.

One cannot conclude from these results that RSV infection is not a risk factor for the development of asthma. The primary host cells in the human airway for RSV are not DCs but epithelial cells. A number of inflammatory cytokines and chemical mediators, including granulocyte/macrophage colony-stimulating factor, a growth factor for DCs, are secreted by airway epithelial cells after RSV infection (45, 46). Mice that genetically express high amounts of granulocyte/macrophage colony-stimulating factor in the lung exhibit a significant increase in pulmonary DCs and show severe allergic airway inflammation (47). Thus, granulocyte/macrophage colony-stimulating factor produced by RSV-infected airway epithelial cells may enhance Th2 response. Taken together, the outcome of the immunologic response, that is, Th1 or Th2, in allergen-sensitized host against RSV infection may be dependent on the balance between the direct effects of RSV infection on DCs and the indirect effects of RSV infection through the production of inflammatory molecules from RSV-infected airway constitutive and inflammatory cells, such as epithelial cells and macrophages.

In conclusion, this study clearly showed that RSV infection attenuates D. farinae-induced Th2-dominant allergic responses at least when RSV directly infected DCs. Further studies are necessary to determine the indirect effects of RSV on DCs through the production of inflammatory mediators from other types of RSV-infected cells.


   Acknowledgments
 
The authors thank Dr. F.G. Issa for the careful reading and editing of the manuscript.


   FOOTNOTES
 
Supported by a Grant-in-Aid for Scientific Research (No. 14770275) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology.

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Conflict of Interest Statement: Y.K. has no declared conflict of interest; H.M. has no declared conflict of interest; I.M. has no declared conflict of interest; T.K. has no declared conflict of interest; S.S. has no declared conflict of interest; S.T. has no declared conflict of interest; Y.O. has no declared conflict of interest; C.F. has no declared conflict of interest; S.K. has no declared conflict of interest.

Received in original form May 16, 2003; accepted in final form November 24, 2003


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 DISCUSSION
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