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IMMUNOBIOLOGY
From Unité INSERM U416, IFR 17, Institut Pasteur
de Lille, France; Department of Applied Genetics, Université
Libre de Bruxelles, Gosselies, Belgium; Department of Microbiology,
University of Western Australia, Nedlands, Perth, Australia; and
Département de Pneumologie, Hôpital A. Calmette, CHRU de
Lille, Lille Cedex, France.
The polarization of the immune response toward a Th2 or a Th1
profile can be mediated by dendritic cells (DCs) following antigen presentation and interaction with T cells. Costimulatory molecules such
as CD80 and CD86 expressed by DCs, the polarizing cytokine environment
during DC-T-cell interaction, and also the nature of the antigen are
critical in the orientation of the immune response. In this study, the
effect of the cysteine protease Der p 1, one of the major allergens of
the house dust mite Dermatophagoides pteronyssinus, on
these different parameters was evaluated comparatively on
monocyte-derived DCs obtained from healthy donors, from
pollen-sensitive patients, or from patients sensitive to
Dermatophagoides pteronyssinus. Results showed that Der p 1 induced an increase in CD86 expression only on DCs from house dust
mite-sensitive patients. This was also associated with a higher
capacity to induce T-cell proliferation, a rapid increase in the
production of proinflammatory cytokines, tumor necrosis factor- Dendritic cells (DCs) are considered the most
powerful antigen-presenting cells (APCs) and play a central role in the
initiation of primary immune responses and in the enhancement of
secondary immune responses. DCs differ from other APCs such as B cells, monocytes, or macrophages by their unique capacity to stimulate naive T
cells in vivo1 and in vitro2 and to induce
the polarization of the immune response toward a Th1 or a Th2 profile.
These 2 types of T-lymphocyte responses differ on the basis of the
cytokine production and also on the functional effects that Th1 and Th2 cells are able to exert after their contact with the
antigen.3 Basically, Th1 cells are considered interferon
(IFN)- DCs can carry processed antigen from nonlymphoid tissues to the
draining lymph node, where they become able to stimulate naive T cells and play a role in their instruction to become Th1 or Th2
cells.4-5 Many factors are important for the determination of the differentiation into Th1 and Th2 cells. In addition to the type
and the dose of antigen, the route of exposure, and the genetic
background of the host, the most critical factors remain (1) the
type of DCs involved in the interaction with naive T cells, (2)
the type of costimulatory molecules expressed on the surface of the
DCs, and (3) the polarizing cytokine microenvironment during antigen presentation.
It is suggested that the type of costimulatory molecules expressed on
DCs are essential for determining Th differentiation. CD86 seems to be
more important than CD80 in the induction of a Th2
response.6 Indeed, in mice exposed to ovalbumin aerosols, treatment with anti-CD86 but not with anti-CD80 significantly inhibits
the 3 features of the allergic reaction In addition, it has been reported that DCs can induce either Th1 or Th2
responses depending on their origin. In humans, DC1 derived from
monocytes induces Th1 responses, whereas DC2 generated from
plasmacytoid monocytes cultured in vitro with CD40L induces Th2
responses.11 However, it is also clear that myeloid DCs can give rise to either DC1 or DC2 depending on the nature of stimulus
influencing the production of IL-12.12 IL-12, the critical Th1-polarizing cytokine,13 can be produced by DCs
incubated with bacterial components such as lipopolysaccharide
(LPS)14 or with CD40L.15 Lastly, IL-10 is
able to down-regulate DC-derived IL-12 production,16
leading to a type 2 response.
It has been postulated that some allergens may influence allergic
responses by noncognate interactions. Thus, Der p 1, a major allergen of the house dust mite Dermatophagoides
pteronyssinus, inhibits the secretion of IFN- PBMC preparation and Der p 1 preparation
Differentiation and antigen loading of DCs
For experiments carried out in the presence of Der p 1, generated DCs were pulsed for 24 hours with 0, 10, and 100 ng/mL Der p 1; with the proenzymatic and inactive form of Der p 1, ProDer p 1 (provided by SmithKline Beecham Biologicals, Rixensart, Belgium),18 using the same protocol; or with 1 µg/mL LPS for 24 hours as a control of DC maturation. DC surface marker analysis Cells were collected, washed in phosphate-buffered saline, and incubated for 30 minutes at 4°C with different monoclonal antibodies (mAbs) (all from Becton Dickinson, Mountain View, CA): fluorescein isothiocyanate (FITC)-conjugated anti-CD80 or anti-CD1a; phycoerythrin (PE)-conjugated anti-CD86, anti-CD11c, or anti-CD83; Cy-chrome-conjugated anti-HLA-DR; or an irrelevant mAb of the same isotype (Becton Dickinson). After washing, the cells were fixed in phosphate-buffered saline-1% paraformaldehyde and analyzed using a FACSCalibur (Becton Dickinson).Cytokine assay Supernatants of 1 × 106 generated DCs pulsed or not with Der p 1, ProDer p 1, or LPS were harvested 6, 24, and 48 hours following stimulation, centrifuged (400g for 7 minutes), and assayed for the presence of tumor necrosis factor (TNF)- , IL-1 ,
IL-6, IL-10, and IL-12 p70 by specific enzyme-linked immunosorbent
assay (ELISA) using Eli-pairs (R&D Systems). The sensitivity of
detection of TNF-, IL-1, and IL-6 was 10 pg/mL; the sensitivity
of detection of IL-10 and IL-12 was 12.5 pg/mL and 6.5 ng/mL, respectively.
Allogeneic proliferation assay Isolation of T cells from PBMCs was performed by depletion of B cells, monocytes, natural killer cells, DCs, early erythroid cells, platelets, and basophils by an indirect magnetic label using a cocktail of hapten-conjugated CD11b, CD16, CD19, CD36, and CD56 antibodies and MACS microbeads coupled to an antihapten mAb (Miltenyi Biotec). The negative cells were collected, washed, and plated at a concentration of 105 cells per well in RPMI 1640-fetal calf serum 10% into 96-well round-bottomed culture plates. Increasing numbers of DCs pulsed or not with Der p 1, ProDer p 1, or LPS were added into the wells containing the allogeneic T cells. Three days later, 3H thymidine (18.5 KBq/well) was added for 16 hours before measurement of the incorporated radioactivity.DC-T-cell cocultures CD4+ T cells were purified from PBMCs after negative depletion of CD14+, CD16+, CD19+, CD56+, and CD8+ cells using MACS microbeads and a MACS column. After 7 days of culture with GM-CSF and IL-4, generated DCs from allergic patients or from healthy donors previously pulsed or not with 100 ng/mL Der p 1 or ProDer p 1 for 24 hours were cocultured with the autologous purified CD4+ T cells at a ratio of 1:10. After 24 or 48 hours of coculture, supernatants were harvested and assayed for IL-4 and IFN- production using a specific ELISA (Diaclone).
Statistical analysis Parametric statistical analysis of cell surface molecule expression and analysis of the cytokine production by DCs were performed using the Student t test. Values of P .05 were considered statistically significant.
Phenotype of monocyte-derived DCs After 7 days of culture with GM-CSF and IL-4, generated cells were analyzed for the expression of DC markers CD1a, CD11c, and HLA-DR. Results show that the cells obtained displayed a high expression of CD1a and CD11c and a low expression of HLA-DR (Figure 1), the costimulatory molecules CD80 and CD86 (Figure 2), and CD83 (Figure 3). This profile is specific for immature DCs.
Effect of Der p 1 on CD80, CD86, and CD83 expression Monocyte-derived DCs from both allergic patients and healthy donors were incubated with 0, 10, or 100 ng/mL Der p 1 for 24 hours. As shown in Figure 2 (1 representative experiment of 7), in the presence of Der p 1 at 100 ng/mL an exclusive increase in CD86 expression was observed on DCs from house dust mite-sensitive allergic patients. In contrast, on DCs from healthy donors and from patients allergic to grass pollen, at the same dose, Der p 1 induced an up-regulation of CD80 expression but not of CD86 expression. In the presence of LPS, DCs from both allergic patients and healthy donors showed an increase in both CD80 and CD86 expression, indicating that the effect observed with Der p 1 was specific to the allergen itself. The effects induced with Der p 1 were not detected at a lower dose.To evaluate the effect of Der p 1 on DC maturation, CD83 expression on unpulsed, Der p 1-pulsed, or LPS-pulsed DCs was measured. As shown in Figure 3, Der p 1 at the dose of 100 ng/mL increased CD83 expression on DCs from only house dust mite-sensitive patients. In response to LPS, DCs from both house dust mite-sensitive patients and healthy donors showed an increase in CD83 expression. Because a difference in the response of DCs issued from allergic patients and healthy donors on costimulatory molecule expression was observed with 100 ng/mL Der p 1, the following experiments were carried out by using only the 100 ng/mL dose. The effect on the costimulatory molecules is dependent on Der p 1 enzymatic activity To evaluate the potential role of Der p 1 enzymatic activity in the modulation of CD80 and CD86 expression, DCs were incubated either with Der p 1 or with the inactive precursor of Der p 1 (ProDer p 1) at 100 ng/mL, the allergen concentration previously shown to efficiently modulate CD80 on DCs from healthy donors and CD86 on DCs from allergic patients. As shown in Figure 2, the up-regulation of CD80 and CD86 observed in Der p 1-pulsed DCs from healthy donors and allergic patients, respectively, was not induced by ProDer p 1.These results suggest that the proteolytic activity of Der p 1 might be involved in the allergen-induced increase in CD80 expression and CD86 expression on DCs from healthy donors or patients allergic to grass pollen and allergic patients, respectively. Proliferation of T cells by DCs When T cells were incubated with unpulsed DCs from either allergic patients or from healthy donors, a low proliferation of T cells was observed. Interestingly, the T-cell proliferative response induced by Der p 1-pulsed DCs from allergic patients (Figure 4A) was higher than the one observed with Der p 1-pulsed DCs from healthy donors (Figure 4B).
DCs from healthy donors pulsed with Der p 1 or with ProDer p 1 were able to induce a similar T-cell proliferation (Figure 4A). Moreover, Der p 1-pulsed DCs from allergic patients showed a better allostimulatory capacity than ProDer p 1-pulsed DCs from allergic patients. Production of cytokines by Der p 1-stimulated DCs When incubated with 100 ng/mL Der p 1, DCs from allergic patients (n = 8) produced high amounts of the proinflammatory cytokines TNF- (Figure 5A), IL-1, (Figure 5B)
and IL-6 (Figure 5C) as compared with unpulsed cells
(P < .05). This enhancing effect of Der p 1 on the
release of these 3 cytokines already observed after 6 hours remained
significant up to 48 hours (P < .05). In contrast, when
DCs from healthy donors (n = 7) were incubated with the same dose of
Der p 1 (100 ng/mL), a significant increase was observed for TNF
after 6 hours (Figure 5D). This stimulatory effect was transient
because at 24 and 48 hours no further increase was detected. In
addition, after 6, 24, and 48 hours, the production of IL-1 and IL-6
was not modified by the allergen exposure as compared with unpulsed
cells (Figure 5E and 5F, respectively).
Concerning the production of cytokines involved in the orientation of
the immune response, a difference of reactivity toward Der p 1 was also
noticed between DCs from house dust mite-allergic patients and DCs
from healthy donors or patients sensitive to grass pollen. When DCs
from patients sensitive to the house dust mite were incubated with Der
p 1, a significant increase in IL-10 production was observed 6 hours
after the contact with the allergen (P < .05) (Figure
6A), whereas IL-12 production was not
modified by Der p 1 as compared with unpulsed cells (Figure 6B).
However, Der p 1 had a different effect on the production of IL-10 and IL-12 by DCs issued from both grass pollen-sensitive patients and from
healthy donors. Following the incubation with Der p 1, only a very
slight effect was detected on IL-10 production (Figure 6C and 6E,
respectively), whereas a significant increase in IL-12 production was
observed (Figure 6D and 6F, respectively) (P < .05 as
compared with unpulsed cells). Stimulation with LPS showed an increase
in both IL-10 and IL-12 by DCs from both allergic patients and healthy
donors without any statistical difference between allergic and healthy
donors.
Effect of Der p 1-pulsed DCs on the in vitro production of IL-4
and IFN- and
IL-4 by autologous T cells stimulated by Der p 1-pulsed DCs was
analyzed. T cells coincubated with Der p 1-pulsed DCs from house dust
mite-sensitive patients (n = 5) produced large amounts of IL-4
(Figure 7A), whereas IFN- production
was not modified (Figure 7B) as compared with T cells stimulated with unpulsed DCs. The effect induced by Der p 1 is dependent on its enzymatic activity because ProDer p 1-pulsed DCs did not modulate IL-4
or IFN- production by T cells. This suggests that DCs need to be
activated by Der p 1 to induce the amplification of the cytokine
production by autologous T cells. In contrast, after incubation with
autologous Der p 1-pulsed DCs, T cells from healthy donors and from
grass pollen-sensitive patients (n = 5) did not modify their
production of IL-4 (Figure 7C and 7E, respectively) but significantly
increased IFN- production up to 48 hours (Figure 7D and 7F,
respectively).
If Der p 1-pulsed DCs from allergic patients were preincubated with
blocking anti-CD80 or anti-CD86 for 2 hours before coculture with T
cells, IL-4 production was blocked preferentially in the presence of anti-CD86 antibodies. The blockade of both molecules did not completely abolish Der p 1-induced IL-4 production (Table 1).
Costimulation through the CD28/CD80-CD86 pathway is one critical point in the establishment of antigen-driven immune responses. Antigen-specific immune responses are initiated after interaction between T cells and APCs such as DCs, and an efficient activation of T cells requires 2 signals. The first signal is delivered after interaction between T-cell receptor and major histocompatibility complex class II molecules; the second involves costimulatory molecules such as CD80 and CD86. The relevance of the CD28/CD80-CD86 pathway in allergic responses is supported by experimental studies demonstrating the role of CD28 in IgE responses.19 The issue of a potential dichotomy in the ability of CD80 and CD86 to generate a Th1 versus a Th2 response remains to be solved. Until now, the effects of allergens on DC function were not well
described. In this study, we demonstrate that in DCs from allergic
patients incubated with Der p 1, the CD86:CD80 ratio was higher than in
DCs from healthy donors that preferentially showed an up-regulation of
CD80 expression. CD86 molecule plays an important role in allergic
diseases and has been shown to be up-regulated on B cells from allergic
patients.20 In contrast, CD80 seems to be preferentially
associated with Th1-type T-cell responses. For example, DCs interacting
with Mycobacterium tuberculosis antigens are activated and
highly express CD80.21 In leishmaniasis, an antigen
homolog to the eukaryotic initiation factor 4A described as an inducer
of Th1-type responses was shown to increase CD80 (B7.1)
expression on normal human monocyte-derived DCs.22 In this
study, we also show that Der p 1 induces an increase in CD86 on DCs
from allergic patients that is dependent on the enzymatic activity of
Der p 1 because the up-regulation of CD86 is abolished using the
cysteine protease inhibitor E64 (data not shown) or the proenzymatic
form of Der p 1, ProDer p 1. This dependency on the catalytic activity
has already been shown to be critical in other noncognate interactions
reported for the allergen, such as the inhibition of IFN- In the present study, DCs from allergic patients exposed to Der p 1 were shown to increase the production of the proinflammatory cytokines
TNF The orientation toward a Th1 or a Th2 profile is also dependent on the
cytokines present when the interaction of DCs with T cells occurs. Many
cytokines are very efficient in focusing the immune response toward a
Th1 or a Th2 profile. IL-10 is known to be a cytokine that inhibits
type 1 responses, thus promoting a type 2 response.28 In
contrast, IL-12 is an inducer of IFN- Taken together, these data suggest that in the presence of the same antigen, the polarized immune response is highly dependent on the immune status of the donor. Indeed, DCs from allergic patients, in contrast with DCs from healthy donors, exposed to Der p 1 play a pivotal role in the amplification of a Th2 response because, in our study, T cells issued from the donors are already primed. Thus, a potential dysregulation at the level of the DCs in allergic patients might be responsible for the establishment of the allergic status.
The authors thank Prof B. Wallaert, Dr C. Lamblin-Degros, and the personnel of the Calmette Hospital (Service et Consultations d'Immunoallergologie) for the selection of patients and the blood collection involved in this study. A.-S. Charbonnier is an HMRGIP recipient.
Submitted December 26, 2000; accepted April 24, 2001.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Joël Pestel, INSERM U416-Institut Pasteur de Lille, 1, rue du Professeur Calmette, B.P.245, 59019 Lille Cedex, France; e-mail: joel.pestel{at}pasteur-lille.fr.
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© 2001 by The American Society of Hematology.
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Top
Abstract
Introduction
namely, the production of
ovalbumin-specific IgE and IgG1 antibodies, airway eosinophilia, and
airway hyperresponsiveness.
, unpulsed cells; 
, Der p 1-pulsed cells; 
, ProDer p
1-pulsed cells; 
, LPS-pulsed cells. Mean ± SEM values
are shown.
,
unpulsed DCs; 
, ProDer p 1-pulsed DCs.
Results are expressed as the mean ± SEM.
*P < .05.
, LPS-pulsed
cells. Results are expressed as the mean ± SEM.
*P < .05.
