* Unité INSERM U416, IFR 17, Institut Pasteur de Lille, Cedex, France;
Erasmus University of Rotterdam, The Netherlands;
Department of Microbiology, University of Western Australia, Nedlands, Perth;
Aventis Pharmaceuticals, Bridgewater, New Jersey; and
¶ Department of Pneumology, Hôpital A. Calmette, CHRU de Lille, Cedex, France
Correspondence: Anne-Sophie Charbonnier, Unité INSERM U416, Institut Pasteur de Lille, 1 rue du Professeur Calmette, B.P. 245, 59019 Lille Cedex, France. E-mail: anne-sophie.charbonnier{at}pasteur-lille.fr
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high/IL-4low] and Der p 1-pulsed P-DC, a Th2 profile (IFN-low/IL-4high). In healthy donors, no T cell polarization (IFN-low/IL-4low) was induced by Der p 1-pulsed M-DC or P-DC, but in response to Der p 1-pulsed M-DC, T cells secreted IL-10. The neutralization of IL-10 produced by Der p 1-pulsed M-DC from healthy donors led to an inhibition of IL-10 production by T cells and a polarization toward a type 1. Thus, IL-10 produced by M-DC might be an essential mediator controlling the balance between tolerance and allergic status. In addition, P-DC could contribute to the steady state in healthy donors or to the development of a Th2 response in allergic donors.
Key Words: allergy • steady state • Th1/Th2 response
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In the allergic context, we recently demonstrated that the allergic status of the donor defines the T cell response induced by relevant allergen-pulsed MDDC: MDDC, issued from healthy subjects pulsed with Der p 1, one of the major allergens of Dermatophagoides pteronyssinus (Dpt), favor a Th1 response, whereas Der p 1-pulsed MDDC issued from Dpt-sensitized allergic patients favor a Th2 response [19 ]. This last Th2 response was reported to be maintained in the presence of IL-12, a Th1-inducing cytokine [20 , 21 ]. In vivo, some observations suggest that DC play a crucial role in the establishment of the allergic inflammatory reaction: Their number increases in the lung of asthmatic patients [22 , 23 ]; bronchial epithelial DC issued from asthmatic patients activate CD4+ T cells with a preferential secretion of Th2 cytokines such as IL-4 and IL-5 [22 ]; a selective DC depletion in ovalbumin (OVA)-sensitized mice leads to a decrease in the immunoglobulin (Ig)E production, an abolition of the Th2 response and a lack of eosinophil recruitment, three elements characterizing the pulmonary allergic response [24 ]; and in rats, freshly isolated respiratory tract DC pulsed with OVA and reinjected in animals stimulate Th2 cells [25 ].
Until now, few data have considered the role of P-DC in the human allergic inflammatory response: In circulation, P-DC cell number positively correlates with serum IgE levels and blood eosinophil counts [26 ]; during experimental allergic rhinitis, an accumulation of P-DC in the vicinity of high endothelium venules was observed in human nasal mucosa [27 ], suggesting their involvement in the triggering of upper airway allergy.
To define a potential dysfunction of M-DC and/or P-DC leading to the allergic reaction, we investigated their respective response to the allergen Der p 1, one major allergen of Dpt. To this end, effects of Der p 1 on M-DC and P-DC in terms of in vitro maturation capacity and consequences on the T cell polarization were analyzed, and behaviors of DC recovered from allergic and healthy donors were compared.
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Donors
Two groups of donors were selected: allergic patients and healthy donors. Twenty-one allergic patients without any treatment were suffering from perennial rhinitis and/or allergic asthma and exhibited positive skin prick tests toward Dpt extracts and specific IgE for Dpt (radioallergosorbent test class 
2). Total IgE level was above 100 kU/L (between 105 and 1347 kU/L), and levels of specific IgE for Dpt were between 1.4 and 98 kU/L. Twenty-seven healthy donors displayed a total IgE level <91 kU/L (between 5 and 70.8 kU/L) without any detection of specific IgE for Dpt in their serum (<0.35 kU/L).
Rhodamine (Rhod) labeling of Der p 1
Der p 1 (Mr=25,000) was labeled with Rhod using Fluoreporter® tetramathylrhodamine protein labeling kit (Molecular Probes, Eugene, OR) following the manufacturer’s instructions. Briefly, the Rhod solution was added to the Der p 1 solution (1 mg/ml) and incubated for 1 h at room temperature in the dark under stirring. The solution was further extensively dialyzed against phosphate-buffered saline (PBS). The Rhod-labeled Der p 1 (Rhod-Der p 1) solution was stored at 4°C and protected from light until use.
Cell preparations
PB mononuclear cells (PBMC) were obtained from whole blood by density gradient over Ficoll-Hypaque (Pharmacia, Saint Quentin en Yvelines, France). PBMC (5–10x107) were recovered from 60 ml whole blood. PB-DC were purified with the blood DC isolation kit (Miltenyi Biotech, Bergisch Gladbach, Germany). PB-DC were pre-enriched from PBMC by depletion of B cells, T cells, monocytes, natural killer (NK) cells with haptenized CD19, CD3, CD11b, and CD16 antibodies, and an anti-hapten mAb coupled to magnetic cell sorter microbeads. The magnetically labeled cells were removed in a magnetic field. PB-DC were purified from the remaining nonbound cell fraction by a positive immunoselection procedure with anti-CD4 mAb-coated magnetic microbeads. For some experiments, M-DC and P-DC were purified using the blood DC isolation kit and the BDCA-4 cell isolation kit (Miltenyi Biotech). After the B cell-, T cell-, monocyte-, and NK cell-depletion step, as described above, P-DC were purified by a positive immunoselection procedure with anti-BDCA-4 mAb-coated magnetic microbeads, which recognized P-DC specifically [30
]. Then, M-DC were purified from the remaining nonbound cell fraction by a positive immunoselection procedure with anti-CD4 mAb-coated magnetic microbeads. P-DC (2.5–7x105; Lin-1-CD123+HLA-DR+CD11c-) and M-DC (0.75–3x105; Lin-1-CD123-HLA-DR+CD11c+) were obtained as determined by immunostaining with a FITC-labeled Lin-1, PE-labeled CD123, CychromeTM-labeled HLA-DR, and APC-labeled CD11c with a purity of 90%. Naive CD4+ T cells were purified by anti-CD11b/CD16/CD19/CD36/CD56/CD8/CD45RO depletion using the pan T cell isolation kit and CD45RO and CD8 beads from Miltenyi Biotech (purity >90%).
Antigen uptake assay
Purified PB-DC were resuspended in the uptake buffer [45% RPMI, 50% PBS, 5% fetal calf serum (FCS)] at a density of 1–3 x 106 cells/ml. PB-DC were prewarmed at 37°C or kept on ice for 20 min. Before use, Rhod-Der p 1 and FITC-Dextran were spun down in a microfuge to eliminate aggregates. On the basis of previous observations on MDDC [31
], PB-DC were incubated for 1 h with 50 µg/ml Rhod-Der p 1, dialyzed Rhod, or 50µg/ml FITC-Dextran at 4°C or 37°C. Then, PB-DC were collected and washed three times with ice-cold PBS. Rhod-Der p 1- and Rhod-pulsed cells were triple-stained with anti-Lin-1 FITC, anti-HLA-DR CychromeTM, and anti-CD11c APC, and FITC-Dextran-pulsed cells were triple-stained with anti-Lin PtdEtn, anti-HLA-DR CychromeTM,and anti-CD11c APC. Antigen uptake by M-DC and P-DC was immediately determined by flow cytometry by gating cells on Lin-1-HLA-DR+CD11c+ (M-DC) and Lin-1-HLA-DR+CD11c- (P-DC) and measuring the mean Rhod-Der p 1 or the FITC-Dextran fluorescence intensity.
PB-DC culture
Purified PB-DC, M-DC, or P-DC were cultured in RPMI-1640 medium containing 10% FCS, 2.5 mM L-glutamine, 100 U/ml penicillin, and 100 µg/ml streptomycin. Cells were seeded at a density of 0.5 x 106/ml in 24-well culture plates (Costar, Brumath, France). Cell suspensions were cultured for 1 day in three different conditions: without any additive stimulus as negative control, after addition of 1 µg/ml Der p 1, or 1 µg/ml LPS as positive control for DC maturation. In some experiments, blocking anti-IL-10 mAb (10 µg/ml) or isotype-matched control Ab (10 µg/ml) was added to the culture. Then, cells were immediately analyzed or cocultured with allogeneic naive CD4+ T cells from healthy subjects for 5 days (T cell:DC ratio was 20:1).
Cell-surface marker analysis
For four-color immunolabeling, cells were washed twice in ice-cold PBS and incubated in 100 µl PBS containing appropriate fluorochrome-labeled mAb for 30 min on ice. At least 20,000 cells were analyzed on a FACScanTM (Becton Dickinson). The analysis of cell-surface markers (CD80, CD86, HLA-DR) on PB-DC was performed by gating cells on HLA-DR+CD11c+CD123low (M-DC) and HLA-DR+CD11clowCD123+ (P-DC) as described previously [32
].
Evaluation of cytokine secretion
IL-10 and IL-12 (p70) production by M-DC and P-DC were measured in supernatants by enzyme-linked immunosorbent assay (ELISA; Diaclone, Besançon, France). IL-4, IFN-, and IL-10 production by T cells cocultured with M-DC or P-DC was measured in supernatants by ELISA (Diaclone).
Statistical analysis
Nonparametric statistical analysis of cell-surface molecule expression and cytokine production by M-DC and P-DC was performed using the Mann-Whitney test. Values of P 
0.05 were considered statistically significant.
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Figure 1. Der p 1 is taken up more by M-DC than P-DC. After purification, PB-DC from allergic patients or from healthy subjects were incubated for 1 h with 50 µg/ml Rhod-Der p 1 (A and B) or FITC-Dextran (C and D) at 4°C (open bars) or 37°C (solid bars). The Der p 1 uptake is given as the fluorescence intensity geometric mean of Rhod-Der p 1 minus dialyzed Rhod of individual subpopulations M-DC (A) or P-DC (B). The FITC-Dextran uptake is given as the fluorescence intensity geometric mean of FITC-Dextran of individual subpopulations M-DC (C) or P-DC (D). Mean ± SEM values obtained in four independent patients are shown.
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Figure 2. HLA-DR expression by cultured PB-DC. After purification, PB-DC from allergic patients (open symbols, A and C) or from healthy subjects (solid symbols, A and C) were immediately analyzed by three-color flow cytometry (NS, circles) or incubated in unsupplemented medium (diamonds), supplemented with Der p 1 (1 µg/ml; squares) or with LPS (1 µg/ml; triangles) for 1 day. Data represent the mean fluorescence intensity (MFI) ± SEM for HLA-DR of M-DC (A and B) or P-DC (C and D). Data of individual donors are shown; means are indicated by bold lines. *, P < 0.05.
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Figure 3. Costimulatory molecule expression pattern of cultured PB-DC subsets issued from allergic patients (A and B) or healthy subjects (C and D). After purification, PB-DC were incubated in unsupplemented medium, supplemented with Der p 1 (1 µg/ml) or with LPS (1 µg/ml) for 1 day, and then analyzed by four-color flow cytometry. Closed histograms represent the anti-CD80 and the anti-CD86 immunoreactivity of M-DC (A and C) or P-DC (B and D). The reactivities of isotype-matched control mAb with the same PB-DC subpopulations are shown by open histograms. One representative independent patient of three (allergic) and five (healthy) is shown.
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Figure 4. IL-10 production by each cultured PB-DC subset. After purification, M-DC (A) or P-DC (B) from healthy donors (n=5) or from allergic patients (n=4) were incubated in unsupplemented medium (light shaded bars), supplemented with Der p 1 (1 µg/ml; dotted bars) or with LPS (1 µg/ml; solid bars) for 1 day. Supernatants were collected, and the amounts of IL-10 were measured by ELISA. Results shown are expressed as the mean ± SEM.*, P < 0.05.
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and IL-4 production in supernatants of coculture with DC from allergic or healthy donors and allogeneic naive CD4+ T cells from healthy donors. Naive T cells cultured with Der p 1-pulsed M-DC from allergic patients secreted pronounced IFN- amounts and low levels of IL-4, corresponding to a Th1-response profile, similar to T cells stimulated with LPS-pulsed M-DC (Fig.5 A
and B
). In contrast, in healthy subjects, Der p 1-pulsed M-DC did not significantly modify IFN- and IL-4 production observed with unpulsed M-DC (Fig. 5 C
and 5D)
. LPS-pulsed M-DC induced a weak increase in IFN- production and no increase in IL-4 secretion. It is interesting that a different profile response was obtained with P-DC. Der p 1-pulsed P-DC from allergic patients led to a low production of IFN- and an increase in IL-4 production, corresponding to a Th2-response profile (Fig. 5 A
and 5B)
. If P-DC were previously pulsed with LPS, then the IL-4 and IFN- production was increased. Control experiments indicated that IL-4 was produced during coculture only when T cells were incubated with P-DC (data not shown). In addition, P-DC stimulated with Der p 1 or LPS did not secrete IL-4, suggesting that the IL-4 production observed in P-DC:T cell coculture was produced by T cells. In healthy subjects, in response to Der p 1, P-DC led to a low secretion of IL-4 and IFN- production (Fig. 5 C
and 5D)
. Thus, in response to Der p 1, M-DC from allergic patients polarized the T cell response toward a type 1 profile, and P-DC primed the polarization of the T cell response toward a type 2 profile. In contrast in healthy subjects, none of M-DC and P-DC was able to polarize T cell response in response to Der p 1.
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Figure 5. Cytokine secretion profile of naive T cells stimulated with M-DC or P-DC depends on the allergic status of the donor. M-DC, P-DC, and mixed PB-DC from allergic patients (A, B, E, and F; n=5) or from healthy donors (C, D, E, and F; n=5) were incubated in unsupplemented medium (light shaded bars), supplemented with Der p 1 (1 µg/ml; dotted bars), or with LPS (1 µg/ml; solid bars) for 1 day. Then, they were cocultured with naive CD4+ T cells for 5 days. Supernatants were harvested and (A, C, and E) IFN- or (B, D, and F) IL-4 was measured by ELISA. Results shown are given as mean ± SEM values. *, P< 0.05.
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and IL-4 production by T cells (Fig. 5 D
and 5F)
. This result suggests that in allergic patients, one DC subset might repress the function of the other DC subset.
The absence of T cell polarization in response to Der p 1-pulsed M-DC from healthy subjects is IL-10-dependent
As IL-10 secreted by DC was reported playing a critical role in the establishment of tolerance, the eventual role of IL-10 produced by Der p 1-pulsed M-DC from healthy subjects in the absence of T cell polarization was determined by neutralizing IL-10 production. The IL-10 neutralization did not affect the expression of DC maturation markers such as HLA-DR, CD40, CD80, and CD86 (data not shown). In contrast, the addition of the blocking anti-IL-10 mAb to Der p 1-pulsed M-DC led to an increase in the IFN- but not in the IL-4 production by naive T cells, characterizing a Th1 profile (Fig . 6
). It is worthy of note that in this neutralization condition, the IFN- amount reached the same levels as those observed with Der p 1-pulsed M-DC from allergic patients (data not shown). In contrast, the isotype-matched control Ab did not modify the cytokine secretion profile of T cells stimulated by Der p 1-pulsed M-DC. In allergic patients, the anti-IL-10 mAb did not modify the Th1 response induced by M-DC (data not shown). These results suggest that IL-10 secreted by Der p 1-pulsed M-DC from healthy subjects should be responsible for the lack of Th1 response by naive T cells.
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Figure 6. Endogeneous IL-10 inhibits the capacity of Der p 1-pulsed M-DC from healthy subjects to initiate a Th1 response. M-DC from healthy donors (n=6) were incubated with Der p 1 in the absence (densely dotted bars), in the presence of mouse IgG2b isotype control (spaced, dotted bars), or blocking anti-IL-10 mAb (hatched bars) for 1 day. Then, they were cocultured with naive CD4+ T cells for 5 days. Supernatants were harvested, and IFN- and IL-4 were measured by ELISA. Results shown are given as an index of increase corresponding to the mean ± SEM values of ratio of cytokine amount in tested coculture supernatant over cytokine amount in Der p 1-pulsed M-DC:T cell coculture supernatant. *, P < 0.05.
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Figure 7. The IL-10 produced by Der p 1-pulsed M-DC from healthy subjects generates IL-10-producing T cells. M-DC from healthy donors (n=5) were incubated in unsupplemented medium (light shaded bars), with Der p 1 in the absence (densely dotted bars) or in the presence of mouse IgG2b isotype control (spaced, dotted bars), or blocking anti-IL-10 mAb (hatched bars) for 1 day. Then, they were cocultured with naive CD4+ T cells for 5 days. Supernatants were harvested, and IL-10 was measured by ELISA. Results shown are given as mean ± SEM values. *, P < 0.05.
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At first, we showed that M-DC were able to capture Der p 1. In allergic patients, the capacity to capture the allergen was not disturbed when compared with healthy donors. In addition, no differences in the phenotype (CD80, CD86, HLA-DR) of freshly isolated M-DC were observed between the two groups. Among maturation markers analyzed, HLA-DR and CD86 were similarly up-regulated in both groups. However, a major difference in the CD80 expression was detected in response to Der p 1 between allergic and healthy donors: Only M-DC from healthy donors significantly increased in their CD80 expression. It is interesting that similar observations were done with Der p 1-pulsed DC derived from monocytes: Those from healthy donors display CD80 up-regulation, whereas those from allergic patients maintain a low CD80 expression level [19 ]. In allergic patients, the lack of CD80 up-regulation is in keeping with other data obtained in vivo, which showed that following an allergen challenge in asthmatic patients, CD80 was not up-regulated on alveolar macrophages and on B cells [33 , 34 ].
Surprisingly, the up-regulation of CD80 expression on Der p 1-pulsed M-DC from healthy subjects did not lead to a T cell polarization. However, unlike allergic patients, Der p 1-pulsed M-DC from healthy donors secreted IL-10, which inhibits the capacity of M-DC to polarize naive T cells and promotes M-DC to generate IL-10-secreting T cells. In mice, T regulatory cells (Tr1), which are involved in the tolerance process, are characterized by a high production of IL-10 [35 ]. In humans, also, in vitro studies show that MDDC-secreting IL-10 generates T cells that display similar characteristics to Tr1 cells [36 37 38 ]. So, IL-10 should be a crucial cytokine in healthy donors to convert M-DC into tolerogenic DC. In the allergic context, pretreatment with IL-10 of MDDC from allergic patients incubated with the appropriate allergen inhibits the production of Th1 and Th2 cytokines by T cells [39 ]; in mouse, pulmonary DC from mice exposed to OVA transiently produced IL-10, which is critical for the induction of tolerance [40 ]; and IL-10-/- mice have more eosinophilic airway inflammation [41 ]. So, IL-10 plays a critical role in the establishment of tolerance against an allergen, and the IL-10 production by Der p 1-pulsed M-DC could be an important source of IL-10 involved in the establishment of the tolerance against Der p 1 in healthy donors. It is worthy of note that the tolerance process is accompanied with a M-DC maturation, as it was described in a mouse model of asthma with pulmonary DC [40 ]. Thus, the tolerance against an allergen in healthy donors would be induced by mature DC in contrast to other tolerance mechanisms involving immature DC expressing low amounts of costimulatory molecules [38 ].
In contrast, in allergic patients, it appears that the lack of IL-10 secretion by Der p 1-pulsed M-DC correlated with the capacity to activate allogeneic T cells and prime naive T cells to a more prominent Th1 polarization. It was already shown that the neutralization of IL-10 secreted by MDDC allows the induction of a Th1 response [36
]. So, in allergic patients, the absence of IL-10 secretion by Der p 1-pulsed M-DC should favor the development of a Th1 response. Recently, Salvi et al. [42
] claimed that "the Th2 hypothesis for asthma" is too simplistic, as evidence argues for the presence of a Th1 response. The presence of IFN-, a Th1 cytokine, in bronchoalveolar lavage and in blood correlates with asthma severity [42
43
44
45
]. In addition, in a mouse model of asthma, Randolph et al. [45
] demonstrated that antigen-specific Th1 cells, which predominate early in the response, are not protective but rather potentiate the allergic inflammatory response. Thus, our results suggest that M-DC from allergic patients could dysregulate the tolerance against an allergen and initiate the Th1 response involved in an allergic inflammatory response. Surprisingly, M-DC from allergic patients did not secrete IL-12, a major cytokine inducing a Th1 response. DC need at least two signals, such as CD40 ligand (CD40-L) and IFN-, to produce IL-12 [46
]. Here, M-DC received only one signal, LPS or Der p 1, which should not be enough for inducing IL-12 production.
It is interesting that in another experimental model, we have previously reported that Der p 1-pulsed MDDC amplify the Th2 response in a syngeneic total T cell population [19 ]. In this last study, we elucidated the recall response mechanism, whereas here, we analyze the initiation of the allergic-immune response with freshly isolated blood M-DC and naive T cells. The comparison of our experimental human models allows us to suggest that also in humans, a Th1 response could occur during the initiation of the allergic response with the involvment of M-DC, and then, a Th2 response takes place, characterizing the recall response. In addition, we have recently observed that the mannose receptor was involved in the Der p 1 uptake by MDDC [31 ]. The inabitity of M-DC to uptake FITC-Dextran and their lack of mannose receptor expression suggest that M-DC should capture Der p 1 in a different way than MDDC. Recent data suggest that the internalization pathway influences the T cell polarization process induced by DC [47 ]. Thus, MDDC and M-DC induce different T cell responses, probably as a result of their different Der p 1 capture pathways.
With P-DC, a low Der p 1 capture was observed in healthy and allergic donors. Also, after 24 h incubation with Der p 1, no maturation marker expression, such as HLA-DR, CD80, or CD86, was detected in allergic as well as healthy donors. However, unlike healthy donors, Der p 1-pulsed P-DC from allergic patients in contact with naive T cells led to the priming of a Th2 polarization. It is well known that in vitro, in response to CD40-L, P-DC mature and polarize naive T cells toward a type 2 profile [4 ]. Thus, Der p 1-pulsed P-DC from allergic patients may induce a Th2 response in contact with naive T cells via the interaction CD40-CD40-L. Recent studies described that in allergic patients, the P-DC number positively correlates with serum IgE levels and blood eosinophil counts [24 ], and in vivo allergen challenge induces P-DC recruitment in the nasal mucosa [27 ], where they are in contact with the allergen. Our results suggest that if they migrate into the lymph node, P-DC would be responsible for the induction of an allergen-specific Th2 response.
In addition, it is worthy of note that in response to LPS, P-DC from allergic patients induced a Th2 response. Until now, such a response to LPS was not reported as a result of the absence of Toll-like receptor 4 (TLR-4) expression on the surface of P-DC [48 ]. This unusual response to LPS allows us to hypothesize that in allergic patients, the LPS receptor profile, such as TLR expression, might be different in comparison to healthy donors.
P-DC also act as type 1 IFN-producing cells to alert the immune system to dangers, in response to viruses such as influenza virus or HSV [12
, 15
]. The IFN-
, known to favor a Th1 response [15
], was detected at very low levels in culture supernatants (data not shown) in response to Der p 1 in allergic as well as in healthy donors. Indeed, Der p 1-pulsed P-DC from allergic patients did favor a Th2 cytokine profile. So, in healthy donors, Der p 1 did not activate any known function of P-DC, initiation of a Th2 response, and production of type 1 IFN, suggesting that P-DC should contribute to maintain the steady state in response to allergens, whereas in allergic patients, they should contribute to establish the allergic reaction by inducing an allergen-specific Th2 response.
When M-DC and P-DC from allergic patients were mixed and then pulsed with Der p 1, their capacity to polarize T cell responses toward a type 1 and a type 2, respectively, was lost. IL-4 produced by T cells stimulated by Der p 1-pulsed P-DC might inhibit IFN- production as already shown [49
]. However, this lack of in vitro T cell polarization does not reflect the physiological situation where a sequential T cell polarization has been emphasized [45
]. Indeed, in vivo, M-DC and P-DC are present in blood and could be recruited in tissues and/or in lymph nodes by different routes [50
]. Thus, in response to an allergen, M-DC and P-DC could separately polarize T cells toward type 1 and type 2, respectively, in space and/or in time.
In conclusion, we have demonstrated that compared with healthy donors, in allergic patients, M-DC and P-DC display dysfunctions in response to Der p 1 with a capacity to induce a T cell polarization toward a type 1 and a type 2, respectively. Thus, M-DC and P-DC should play a critical role in the establishment of the balance between tolerance and allergic status against an allergen. In healthy donors, in response to Der p 1, P-DC and M-DC do not stimulate naive T cells and might contribute to the steady state, whereas in allergic patients, they dysregulate the T cell response in Dpt-sensitized allergic patients, leading to allergic status.
Received June 11, 2002; revised September 17, 2002; accepted October 13, 2002.
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