Skip Navigation


International Immunology Advance Access originally published online on October 26, 2006
International Immunology 2006 18(12):1789-1799; doi:10.1093/intimm/dxl113
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
18/12/1789    most recent
dxl113v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (10)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Kitawaki, T.
Right arrow Articles by Uchiyama, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kitawaki, T.
Right arrow Articles by Uchiyama, T.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?


© The Japanese Society for Immunology. 2006. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

IgE-activated mast cells in combination with pro-inflammatory factors induce Th2-promoting dendritic cells

Toshio Kitawaki1, Norimitsu Kadowaki1, Naoshi Sugimoto1, Naotomo Kambe2, Toshiyuki Hori1, Yoshiki Miyachi2, Tatsutoshi Nakahata3 and Takashi Uchiyama1

1 Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan
2 Department of Dermatology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan
3 Department of Pediatrics, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan

Correspondence to: N. Kadowaki; E-mail: kadowaki{at}kuhp.kyoto-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Supplementary data
 References
 
Dendritic cells (DCs) and mast cells (MCs) co-localize in peripheral tissues of antigen entry, i.e. skin and mucosa. Due to the proximity of these two cell types, activation of MCs may affect DC functions. Here, we co-cultured human monocyte-derived DCs with cord blood-derived MCs activated by cross-linking of Fc{varepsilon}RI to elucidate the net effect of the whole MC products on DCs. Activated MCs induced maturation of DCs, and potently suppressed IL-12p70 production by the DCs. Whereas co-culture of DCs with activated MCs alone did not significantly influence the type of CD4+ T cell responses induced by the DCs, DCs co-cultured with activated MCs in the presence of pro-inflammatory or Th1-inducing factors caused Th2 polarization. Although histamine was involved in the induction of DC maturation and Th2 polarization by activated MCs, a combinatorial effect of various MC-derived factors, including those acting in a cell contact-dependent manner, was required for the optimal induction of Th2-promoting DCs. Furthermore, we demonstrated that clusters of DCs are located closely with MCs in lesions of atopic dermatitis. Collectively, this study suggests that the interaction between DCs and IgE-activated MCs in a pro-inflammatory or even Th1-prone environment is instrumental in maintaining and augmenting Th2 responses in allergy, and that disruption of the DC–MC interaction may constitute an effective strategy to treat ongoing allergic diseases.

Keywords: allergy, antigen-presenting cells, human, T cells


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Supplementary data
 References
 
Immature dendritic cells (DCs) are located mainly in peripheral tissues through which antigens invade, particularly in skin and mucosa (1). At the initial stage of an immune response, immature DCs are activated directly by pathogens and indirectly by various inflammation-associated factors produced by tissue resident cells in the microenvironment (2). Activation of DCs induces their maturation and migration to secondary lymphoid organs, where the mature DCs prime antigen-specific naive T cells. During the process of maturation, DCs integrate signals from both pathogens and tissue-derived factors and acquire the capacity of inducing different types of CD4+ T cell responses, prototypes of which are Th1 and Th2 types. Thereby, DCs induce appropriate types of adaptive immune responses for efficient elimination of the given pathogens.

Another abundant cell type present in skin and mucosa is mast cells (MCs) (3–6). MCs are well recognized as key effector cells in IgE-associated, Th2-type immune responses. Upon activation by cross-linking of a high-affinity IgER, Fc{varepsilon}RI, MCs immediately undergo degranulation and secrete a vast array of humoral mediators (reviewed in 5, 6). These include preformed granule-associated molecules [e.g. neutral proteases, tumor necrosis factor (TNF)-{alpha} and histamine], de novo synthesized lipid mediators [e.g. prostaglandin D2 (PGD2), leukotriene C4 and B4], cytokines and chemokines. In addition to Fc{varepsilon}RI, MCs express a diverse spectrum of receptors for ‘danger’ signals, such as pathogens and endogenous inflammatory mediators (5, 6). By virtue of their ability to directly sense ‘dangers’ and to immediately secrete a vast array of humoral mediators, MCs play an important role in the first line of defense against microbial invasions as well as in immediate allergic reactions.

Recent studies have been revealing critical roles of MCs in inducing optimal adaptive T cell responses (6). First, MCs, by immediately secreting preformed TNF-{alpha} upon bacterial invasion, induce hypertrophy of draining lymph nodes and recruitment of circulating T cells (7). Second, MCs appear to be critical for the full manifestation of experimental autoimmune encephalomyelitis (8, 9). Third, several studies suggest that MCs migrate to secondary lymphoid organs and influence T cell responses (9–11). Thus, other than an established role as immediate effector cells in allergic responses, MCs are likely to be critically involved in determining the strength and quality of adaptive immune responses.

MCs and immature DCs co-localize at antigen entry sites, i.e. skin and mucosa. Both human and mouse MCs activated by cross-linking of Fc{varepsilon}RI have been shown to express markedly high levels of chemokines that attract immature DCs: CCL2, CCL3 and CCL4 (12, 13). Reciprocally, DCs have been shown to produce CCL5 and CCL8 (14) that can interact with CCR3 on MCs (15). Due to such apparent interaction between the two cell types, a vast array of humoral and possibly membrane-associated molecules derived from MCs may influence DC functions in peripheral inflamed tissues, which leads to modulation of adaptive T cell responses in draining lymphoid organs (6). Indeed, several molecules secreted by MCs have been shown to affect DC functions. First, histamine, which is stored in MC granules and is immediately released upon activation, induce human monocyte-derived dendritic cells (MoDCs) to transiently express CD86 expression (16), to produce more IL-10 and less IL-12 and to differentiate into Th2-promoting DCs (17–20). Second, PGD2, a major eicosanoid from MCs, reduces IL-12 production by MoDCs and favors Th2 development (21, 22). Third, thymic stromal lymphopoietin (TSLP), whose mRNA is expressed in MCs, promote maturation of CD11c+ blood DCs and their differentiation into Th2-promoting DCs (23–25). Lastly, MC-derived exosomes have been shown to induce DC maturation (26). These studies suggest that MCs influence DC functions via different mechanisms. However, MCs express many other secretory and membrane-associated molecules that potentially affect DCs, and the net effect of the whole MC-derived factors on DC function, which will occur in a physiological situation, remains to be determined.

Here, to investigate the effects of the whole MC products on DC functions, we co-cultured human MoDCs with cord blood-derived MCs activated by cross-linking of Fc{varepsilon}RI, and examined DC maturation, cytokine production and naive CD4+ T cell differentiation primed by the DCs. Significantly, whereas co-culture of DCs with activated MCs alone did not have any effect on polarization of T cell differentiation, DCs co-cultured with activated MCs in the presence of other DC maturation-inducing factors polarized T cell responses toward a Th2 type. Although histamine was involved in inducing Th2-promoting DCs, combinatorial effects of other MC-derived factors, including those acting in a cell contact-dependent manner, were required for the optimal induction of Th2-promoting DCs.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Supplementary data
 References
 
Media and reagents
RPMI 1640 (Sigma–Aldrich, St Louis, MO, USA) supplemented with 10% heat-inactivated FCS (ThermoTrace, Victoria, Australia), 2 mM L-glutamine, penicillin G, streptomycin (GIBCO BRL, Carlsbad, CA, USA) and 10 mM HEPES (Nacalai Tesque, Japan) was used (referred to as complete medium). Recombinant human cytokines, IL-3, IL-4, IL-6, IFN-{gamma}, TNF-{alpha} and IL-1ß were purchased from PeproTech (London, UK), and stem cell factor (SCF) was obtained from Amgen (Thousand Oaks, CA, USA). Granulocyte–macrophage colony-stimulating factor (GM-CSF) was obtained from Schering–Plough.

Generation of human umbilical cord blood-derived MCs
Umbilical cord blood was obtained from healthy volunteers in local obstetrics hospitals. Written informed consent was obtained from mothers from whom the cord blood was got, and the procedures were approved by the Human Studies Internal Review Board of Kyoto University. Cord blood-derived MCs were obtained as previously described (27). Briefly, mononuclear cells were isolated from cord blood by centrifugation on Ficoll–Paque (Amersham Pharmacia Biotech, Uppsala, Sweden), and the cells were cultured in AIM-V medium containing 5% FCS in the presence of 100 ng ml–1 SCF and 50 ng ml–1 IL-6 for >10 weeks. Half of the medium was exchanged weekly for fresh medium supplemented with the cytokines. Then, the cells were further incubated with 1 µg ml–1 IgE (Biosource International, Camarillo, CA, USA), 5 ng ml–1 IL-3, 10 ng ml–1 IL-4 for 5 days in the presence of SCF and IL-6. These factors have been shown to act synergistically on cord blood-derived MCs, and prolong survival, induce maturation, enhance Fc{varepsilon}RI expression and optimize secretion of histamine, PGD2 and leukotriene C4 when MCs are activated by cross-linking of Fc{varepsilon}RI (15, 28–32). For the last 3 h of incubation, IgE was added again to assure that IgE binds to Fc{varepsilon}RI, and then IgE-sensitized mature MCs were harvested. MCs obtained by this method were positively stained with toluidine blue and expressed Fc{varepsilon}RI (stained with anti-Fc{varepsilon}RI mAb: clone CRA-1). The purity of MCs was >98% as assessed by the expressions of CD117 (eBioscience, San Diego, CA, USA) and CD203c (Beckman Coulter Immunotech, Marseille, France) by flow cytometry.

Generation of human MoDCs
Buffy coats were obtained from healthy donors in the local blood bank (Red Cross Blood Center, Kyoto, Japan). PBMCs were isolated by centrifugation on Ficoll–Paque. Monocytes were purified from PBMCs by positive selection using anti-CD14-conjugated microbeads (Miltenyi Biotec, Bergisch Gladbach, Germany). Monocytes were cultured for 6–7 days in complete medium in the presence of 40 ng ml–1 IL-4, and 50 ng ml–1 GM-CSF to induce immature MoDCs. Every 3 days, half of the medium was exchanged for fresh medium supplemented with the cytokines.

Co-culture of DCs and MCs
Immature MoDCs and IgE-sensitized mature MCs were co-cultured in complete medium at a density of 5 x 105 DCs ml–1 per well in a 24-well microplate in the presence of 50 ng ml–1 GM-CSF, 40 ng ml–1 IL-4 and 100 ng ml–1 SCF at a DC:MC ratio of 2:1, unless otherwise indicated. For MC activation by cross-linking of Fc{varepsilon}RI, goat anti-human IgE antibody (Biosource International) was added at a concentration of 3 µg ml–1, and the co-culture was performed for 24 h. Where indicated, 10 µg ml–1 mouse anti-human TNF-{alpha} mAb (clone: MAb1, BD PharMingen, San Diego, CA, USA), a mixture of histamine receptor antagonists or 10 µM indomethacin (Sigma–Aldrich) (33), was added. The following histamine receptor antagonists were combined: 10–7 M pyrilamine (Sigma–Aldrich), 10–4 M cimetidine (a gift from Sumitomo Pharmaceuticals, Osaka, Japan) and 10–6 M thioperamide (Sigma–Aldrich) for H1, H2 and H3 plus H4 receptor blocking, respectively (18, 34). Separation of DCs and MCs by a porous membrane in the co-culture was performed by using transwell culture plates with polycarbonate membrane insert with 0.4-µm pore size (Costar, Corning, NY, USA). In some experiments, DCs were stimulated with 100 ng ml–1 LPS (from Escherichia coli O111:B4, Sigma–Aldrich), 1000 IU ml–1 IFN-{gamma}, 10 ng ml–1 TNF-{alpha}, 10 ng ml–1 IL-1ß and/or 10–5 M histamine (Sigma–Aldrich), with or without MCs. Concentrations of IL-12p70 in 24-h supernatants were measured by the ELISA kits (BD PharMingen). Stimulation of DCs with CD40 ligand (CD40L) was done as described (35), using irradiated (55 Gy) CD40L-transduced L cells.

Measurement of concentrations of MC-derived humoral mediators
IgE-sensitized mature MCs were plated alone at the same density and under the same cytokine condition as the DC–MC co-culture, and were activated by cross-linking of Fc{varepsilon}RI. Concentrations of TNF-{alpha} in 24-h supernatants were measured by an ELISA kit (Biosource International), and those of histamine and PGD2 by enzyme immunoassay kits (Cayman Chemical, Ann Arbor, MI, USA).

Phenotypic analysis of DCs and MCs
The expression of surface markers was analyzed by FACSCalibur (Becton Dickinson, Mountain View, CA, USA) using the following mAbs: FITC-labeled anti-CD80, CD83, CD40, CD54, HLA-ABC and HLA-DR (Beckman Coulter Immunotech); FITC-labeled anti-CD86 (BD PharMingen) and FITC-labeled anti-CCR7 mAbs (R&D Systems, Minneapolis, MN, USA). For cells in DC–MC co-culture, the cells were stained with PE-labeled anti-CD11c mAb (Becton Dickinson), and CD11cbright cells and CD11cdim cells were gated as DCs and MCs, respectively. For OX40 ligand (OX40L), cells were stained with ik-5 mAb (mouse IgG2a) (36) and FITC-labeled F(ab')2 goat anti-mouse IgG antibody (Zymed Laboratories, San Francisco, CA, USA).

Analysis of cytokine production by primed T cells
Naive CD4+ T cells were isolated from human cord blood mononuclear cells with the CD4 isolation kit II or from adult PBMCs with CD4 Multisort kit and CD45RA microbeads (Miltenyi Biotec). This method yielded highly purified (>92%) CD4+ CD45RA+ naive T cells as assessed by flow cytometry (data not shown). Naive T cells (5 x 104 cells) were co-cultured with allogeneic DCs (5 x 103 cells) in complete medium in 96-well round-bottom microplates. DCs co-cultured with MCs were purified by FACSAria cell sorter (Becton Dickinson) by gating CD11cbright population as DCs before they were used to stimulate T cells. On day 3, 10 ng ml–1 IL-2 (teceleukin, Takeda Pharmaceuticals, Japan) was added. T cells were further expanded and subjected to analysis of cytokine production on days 12–14. For intracellular cytokine staining, primed T cells were re-stimulated with 50 ng ml–1 phorbol myristate acetate (PMA) (Sigma–Aldrich) and 500 ng ml–1 A23187 [GenBank] (Calbiochem) for 6 h. Brefeldin A (10 µg ml–1) (Sigma–Aldrich) was added during the last 3 h. The cells were fixed, permeabilized and stained with FITC-labeled anti-IFN-{gamma} mAb (BD PharMingen) plus PE-labeled anti-IL-4 mAb (BD PharMingen). For ELISA, T cells were re-stimulated with PMA/A23187 at 1 x 106 cells ml–1 for 24 h, and the supernatants were harvested. For IFN-{gamma}, a matched antibody pair (clone 2G1 and B133.5; Pierce Biotechnology, Rockford, IL, USA) was used. For IL-4, IL-5, IL-10 and IL-13, commercially available ELISA kits (Biosource International) were used.

Real-time reverse transcription–PCR analysis of Notch ligands
Total RNA was isolated from FACS-sorted DCs after DC–MC co-culture using RNeasy Mini kit (Qiagen, Hilden, Germany). Total RNA (0.5 µg) was reverse transcribed using TaqMan Reverse Transcription Reagents (Applied Biosystems, Tokyo, Japan) according to the manufacturer's protocol. Real-time PCR was performed using qPCR Mastermix Plus (Eurogentec, Belgium) and TaqMan Gene Expression Assays for JAG1, JAG2 and DLL4 (Applied Biosystems) on the ABI PRISM 7700 Sequence Detection System. Relative quantitations of mRNA expressions were performed by the relative standard curve method and mRNA expression levels of each gene were normalized to those of ß-glucronidase.

Immunohistochemical staining
Formalin-fixed, paraffin-embedded sections were prepared from biopsied specimens of lesional skins from patients with atopic dermatitis. After deparaffinization, endogeneous peroxidase activity was blocked by 0.3% H2O2 in methyl alcohol. The slides were pre-incubated with 1% normal horse serum and incubated with anti-human MC tryptase mAb (clone: G3, Chemicon International, Temecula, CA, USA). Subsequently, they were incubated with biotinylated horse anti-mouse serum, and the development of staining was performed using avidin–biotin–peroxidase complex (ABC-Elite, Vector Laboratories, Burlingame, CA, USA) and diaminobenzidine. After incubation with 0.1 M glycine–HCl (pH 2.2) and antigen retrieval by autoclave methods (37), fascin was stained with mouse anti-human fascin mAb (clone: 55K-2, DakoCytomation, Carpinteria, CA, USA) by the same procedure as the above, using avidin–biotin–alkaline phosphatase and New fuchsin in the development step. Using isotype-matched control mAbs instead of the anti-tryptase or anti-fascin mAb did not show non-specifically stained cells.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Supplementary data
 References
 
Activated MC-derived factors induce DC maturation
First, we examined whether the in vitro-generated MCs secrete humoral factors upon activation that have been reported to affect DC functions. IgE-sensitized mature MCs were plated at the same cell density and under the same cytokine condition as the DC–MC co-culture, and activated by cross-linking of Fc{varepsilon}RI. They secreted considerable amounts of TNF-{alpha} (256 ± 0.6 pg ml–1), histamine (6.7 ± 0.6 µM) and PGD2 (21.3 ± 0.86 ng ml–1) for 24 h. As expected, addition of a cyclo-oxygenase inhibitor, indomethacin, inhibited the production of PGD2 by activated MCs, whereas a mixture of histamine receptor antagonists did not affect the secretion of the three factors (data not shown). Thus, the in vitro-generated MCs are physiologically relevant in that they secrete major humoral factors produced by MCs, including the ones which can affect DC functions.

To examine the net effect of the whole activated MC-derived factors on DC functions, we co-cultured IgE-sensitized mature MCs with immature MoDCs, and then activated MCs by cross-linking of Fc{varepsilon}RI by adding goat anti-human IgE antibody. GM-CSF, IL-4 and SCF were added to the co-culture to maintain the viability of DCs and MCs and to optimize mediator release from MCs (32, 38, 39). SCF alone did not induce DC maturation or affect DC maturation induced by LPS (data not shown). First, we analyzed phenotypes of DCs after 24 h of co-culture with activated MCs by flow cytometry, gating CD11cbright population as DCs (Fig. 1). Without activation, MCs had no effect on the phenotypes of the DCs. In contrast, MCs activated by cross-linking of Fc{varepsilon}RI induced up-regulation of CD80, CD86, CD83, CCR7, HLA-ABC and HLA-DR on the co-cultured DCs. Activated MCs did not affect maturation of DCs induced by LPS (Fig. 1) or LPS/IFN-{gamma} (data not shown) added at the same time as the MC activation. These data indicate that activated MC-derived factors induce DC maturation, and that they do not have antagonistic effects on Toll-like receptor 4-mediated maturation of DCs.


Figure 1
View larger version (31K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Activated MC-derived factors induce DC maturation. Immature MoDCs were either cultured alone or co-cultured with IgE-sensitized mature MCs at a DC:MC ratio of 2:1. To activate IgE-sensitized MCs, Fc{varepsilon}RI was cross-linked with goat anti-human IgE antibody. Where indicated, 100 ng ml–1 LPS was added to immature DCs either alone or with activated MCs (at the same time as Fc{varepsilon}RI cross-linking). After 24 h of co-culture, surface phenotypes of DCs were analyzed by flow cytometry. CD11cbright cells were gated and analyzed as DCs. Open histograms indicate background staining with an isotype-matched control mAb. These results are representative of three independent experiments.

 
To investigate relative contributions of each MC-derived factor to DC maturation, we added histamine receptor antagonists, neutralizing anti-TNF-{alpha} mAb or indomethacin (33) to the DC–MC co-culture to block the actions of histamine or TNF-{alpha}, or to inhibit the synthesis of PGD2 in activated MCs, respectively. Because immature MoDCs express histamine H1, H2, H3 and H4 receptors (18, 20, 40), a mixture of antagonists against all the receptors (pyrilamine, cimetidine and thioperamide) was used. In addition, to evaluate the effect of cell contact on DC maturation, we separated DCs from MCs by a porous membrane using transwell plates. Although MCs can also produce IL-4 (4–6), which affects DC function, the addition of exogenous IL-4 to the co-culture precludes us from evaluating the influence of MC-derived IL-4 on DCs. As shown in Fig. 2, up-regulation of co-stimulatory molecules, CD80 and CD86, on DCs was largely inhibited by histamine receptor antagonists, whereas anti-TNF-{alpha} mAb or indomethacin did not show a considerable effect. Separation of DCs and MCs diminished the levels of the up-regulation. These data indicate that histamine is responsible for the up-regulation of co-stimulatory molecules on DCs, whereas TNF-{alpha} and PGD2 are not involved. Cell contact has an augmenting effect on the up-regulation. It remains to be determined whether this augmentation is mediated by membrane-associated molecules on MCs that act in combination with histamine or by possible increases in local concentrations of MC-derived soluble factors around DCs.


Figure 2
View larger version (42K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Contribution of each activated MC-derived factor to the induction of DC maturation. Immature MoDCs and activated MCs were co-cultured, in the same chamber (with cell contact) or separated by a porous membrane (without cell contact) in transwell culture plates. A mixture of histamine receptor antagonists (10–7 M pyrilamine, 10–4 M cimetidine and 10–6 M thioperamide), 10 µg ml–1 neutralizing anti-TNF-{alpha} mAb or 10 µM indomethacin was added to the co-culture as indicated. After 24 h of co-culture, cells were analyzed by flow cytometry as above. Open histograms indicate background staining with an isotype-matched control mAb. Numbers indicate the relative fluorescent intensity of each marker, obtained by dividing the mean fluorescent intensity of each marker by that of the isotype control. aMC, activated mast cells; HRA, histamine receptor antagonists; IND: indomethacin. These results are representative of three independent experiments.

 
IL-12p70 production by DCs is potently suppressed by activated MCs
IL-12p70 is a key DC-derived cytokine that plays a crucial role in induction of Th1 responses (41). Thus, we next examined the effects of activated MC-derived factors on IL-12p70 production by DCs. We co-cultured DCs and MCs, and stimulated DCs with either LPS or CD40L in the presence or absence of IFN-{gamma} to induce IL-12p70 production by DCs (42, 43). At the same time as the DC stimulation, MCs were activated by cross-linking of Fc{varepsilon}RI. After 24 h of culture, concentrations of IL-12p70 in the supernatants were measured by ELISA (Table 1). Stimulation with either LPS or CD40L in the presence or absence of IFN-{gamma} induced variable amounts of IL-12p70 production by DCs, depending on donors. Remarkably, IL-12p70 production by DCs was potently suppressed by activated MCs irrespective of the type of DC stimulation, indicating that activated MCs suppress IL-12p70 production whether DCs are activated by a pathogen-derived signal in the peripheral tissues or by a T cell-derived signal during interaction with T cells. Separation of DCs and MCs only slightly diminished the suppression, indicating that soluble factors play a major role. Histamine receptor antagonists only partially reversed the suppression, and addition of histamine at 10–5 M, the concentration comparable to that produced by activated MCs in this system, was not sufficient to reproduce the suppressive effect of activated MCs, indicating that although histamine plays an important role, combinatorial effects of other MC-derived soluble factors are also present. Although PGD2 has been reported to suppress IL-12p70 production by MoDCs (21, 22), indomethacin did not have a considerable effect on the suppression, even when combined with histamine receptor antagonists, indicating that PGD2 is not a critical factor for the suppression in this culture system. Thus, activated MCs potently suppress IL-12p70 production by DCs mainly through histamine and other synergistic soluble factors except PGD2. Cell contact appears to play only a minor role in this suppression.


View this table:
[in this window]
[in a new window]

  		Table 1 Effects of MC-derived factors on IL-12p70 production by DCsa

 
DCs co-cultured with activated MCs in combination with other maturation-inducing factors induce Th2-promoting DCs
The cytokine profile of CD4+ T cells primed by mature DCs is profoundly affected by signals given to DCs during maturation (2). Thus, we primed allogeneic naive CD4+ T cells with DCs that had been co-cultured with activated MCs in the presence or absence of other maturation-inducing factors: LPS or TNF-{alpha}/IL-1ß. Some of MC-derived factors such as IL-4, histamine and OX40L have been shown to have direct effects on T cells (11, 44). To eliminate direct effects of activated MCs on T cell priming, we purified DCs from the DC–MC co-culture by a cell sorter before they were used to prime T cells. The purity of DCs was always >98% as assessed by the CD11c expression by flow cytometry. After 12–14 days of expansion, the T cells were re-stimulated with PMA/A23187 and their cytokine profiles were analyzed by intracellular cytokine staining for IFN-{gamma} and IL-4 (Fig. 3A).


Figure 3
View larger version (34K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 DCs were polarized toward Th2 by co-culture with activated MCs. (A) Immature DCs were cultured with or without activated MCs in the presence or absence of LPS or TNF-{alpha}/IL-1ß. After 24 h, CD11cbirght cells were sorted as DCs by a cell sorter, and were used to prime cord blood allogeneic naive CD4+ T cells. After 12- to 14-day expansion, T cells were re-stimulated with PMA/A23187, and were analyzed by intracellular cytokine staining for IFN-{gamma} and IL-4. Percentages of cytokine-producing cells are indicated in each quadrant. (B) Immature DCs were cultured with activated MCs at different DC:MC ratios in the presence of LPS for 24 h. The cytokine profile of adult allogeneic naive CD4+ T cells primed by the DCs was analyzed as in (A). (C) Immature DCs were stimulated with LPS/IFN-{gamma} in the presence or absence of either histamine or activated MCs for 24 h. In some co-culture, a mixture of histamine receptor antagonists was added, or DCs and MCs were separated by a porous membrane in transwell plates. The cytokine profiles of cord blood allogeneic naive CD4+ T cells primed by the DCs were analyzed as in (A). (D) Cord blood allogeneic naive CD4+ T cells were primed with the DCs as in (C), and were re-stimulated with PMA/A23187 at 1 x 106 cells ml–1 for 24 h. The concentrations of cytokines in supernatants were measured by ELISA. Error bars indicate standard deviation of duplicate measurements. aMC, activated MCs; His, Histamine; HRA, histamine receptor antagonists; TW, transwell. The results in (A–D) are representatives of three independent experiments.

 
Immature DCs or DCs stimulated with LPS or TNF-{alpha}/IL-1ß mainly induced IFN-{gamma} single-producing Th1 cells with a minor population of T cells exhibiting an IFN-{gamma}/IL-4 double-positive pattern of uncommitted ‘Th0-like’ T cells. Co-culturing DCs with activated MCs in the absence of other maturation-inducing factors did not affect the cytokine profile of T cells. Remarkably, however, when DCs were co-cultured with activated MCs in the presence of LPS or TNF-{alpha}/IL-1ß, the frequency of IL-4 single-producing Th2 cells considerably increased, while the frequency of both Th1 and Th0-like cells decreased. The degree of the Th2-polarizing effect was correlated with the DC:MC ratio, while this effect was still observed at the DC:MC ratio of 32:1 (Fig. 3B). Moreover, the Th2-polarizing effect was observed even when DCs were co-cultured with activated MCs in the presence of LPS/IFN-{gamma}, a combination that strongly induces Th1-promoting DCs (42; Fig. 3C). Thus, IgE-activated MCs, when combined with additional DC maturation factors, induce DCs that diminish Th1 and promote Th2 differentiation.

Activated MCs induce Th2-promoting DCs by combinatorial effects of different factors
We then investigated relative contributions of each MC-derived factor to the induction of Th2-promoting DCs (Fig. 3C). DCs stimulated with LPS/IFN-{gamma} induced IFN-{gamma} single-producing Th1 cells with a minor population of IFN-{gamma}/IL-4 double-producing T cells, as observed with DCs stimulated with LPS or TNF-{alpha}/IL-1ß. DCs co-cultured with activated MCs in the presence of LPS/IFN-{gamma} increased IL-4 single-producing Th2 cells and decreased Th1 and Th0-like cells. Both addition of histamine receptor antagonists and separation of DCs and MCs considerably reduced the Th2 polarization of DCs, indicating that both histamine and cell contact contribute to the induction of Th2-promoting DCs. Importantly, addition of histamine at 10–5 M only slightly antagonized the Th1 induction by DCs stimulated with LPS/IFN-{gamma}. Indomethacin did not have any considerable effect on T cell polarization in accordance with the absence of its effect on activated MC-induced suppression of IL-12p70 production by DCs (data not shown).

We also examined cytokine production by T cells by ELISA (Fig. 3D). CD4+ T cells primed by LPS/IFN-{gamma}-stimulated DCs produced a high level of IFN-{gamma} and low or undetectable levels of Th2 cytokines (IL-4, IL-5 and IL-13) as well as IL-10. Addition of histamine alone slightly suppressed the Th1 induction, as shown by a decrease in IFN-{gamma} production and slight increases in IL-5, IL-10 and IL-13 production. Activated MCs decreased IFN-{gamma} production more potently than histamine, and remarkably increased the production of Th2 cytokines and IL-10 far more than histamine did. Histamine receptor antagonists or separation of DCs and MCs considerably suppressed the production of Th2 cytokines and IL-10, whereas did not significantly increase the IFN-{gamma} production.

The intracellular staining data (Fig. 3A and C) indicate that a considerable number of naive T cells differentiated toward IFN-{gamma}/IL-4 double-producing Th0-like cells in the absence of MCs. Consequently, the overall frequency of IL-4-producing T cells (i.e. Th2 cells plus Th0-like cells) does not change much irrespective of the presence or absence of MCs. However, the ELISA data (Fig. 3D) suggest that IL-4 single-producing Th2 cells induced by MC-stimulated DCs are qualitatively distinguished from IFN-{gamma}/IL-4 double-producing Th0-like cells induced without MCs, because the former T cells appear to produce large amounts of other Th2 cytokines (IL-5 and IL-13) and IL-10, whereas the latter T cells produce little amounts of these cytokines (Fig. 3D). These data indicate that the CD4+ T cells induced by MC-stimulated DCs appear to be truly Th2-polarized cells, and thus such DCs have Th2-promoting activity as well as Th1-suppressing activity.

Collectively, activated MCs, even in the presence of Th1-promoting stimuli (LPS/IFN-{gamma}), induce DCs that suppress Th1 and promote Th2 differentiation by combinatorial effects of different factors, including histamine, other soluble factors except PGD2 and cell contact-dependent factors.

Close anatomical associations between DCs and MCs in atopic dermatitis
Finally, to obtain insights into the DC–MC interactions in vivo, we examined the anatomical relationship between DCs and MCs in inflammatory skin lesions. We visualized DCs and MCs in lesional skins of chronic atopic dermatitis by immunohistochemical staining using anti-fascin mAb for DCs and anti-tryptase mAb for MCs (Fig. 4). Anti-fascin mAb has been reported to react with DCs, endothelial cells and some neuronal cells in central nervous system (45–47). In all of four patients examined, both fascin-positive cells with DC morphology and tryptase-positive cells were detected. Fascin-positive cells were present in the superficial layer of dermis, forming aggregates (Fig. 4A, arrows). Tryptase-positive cells were scattered throughout the dermis, and some of them surrounded the aggregates of fascin-positive cells with a few intermingled with fascin-positive cells (Fig. 4B and C). The anatomical proximity of the two cell types was observed in all patients, suggesting functional associations between DCs and MCs in inflammatory skin lesions.


Figure 4
View larger version (44K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 4 Close anatomical associations between DCs and MCs in atopic dermatitis. A biopsied specimen of lesional skin of atopic dermatitis was immunohistochemically stained by anti-fascin mAb for DCs (red) and anti-tryptase mAb for MCs (brown). (A) Arrows indicate aggregates of fascin-positive cells in the superficial layer of the dermis. Original magnification: x100. (B and C) Magnified views of the aggregates of fascin-positive cells shown in (A). Note that tryptase-positive cells surround the aggregates, and some of them are intermingled with fascin-positive cells. Original magnification: x400. These results are representative of four different patients.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Supplementary data
 References
 
Co-localization of DCs and MCs in sub-epithelial areas as sentinels for invading antigens, and immediate production of a variety of inflammatory mediators by activated MCs, suggest that MCs may influence the type of adaptive T cell immune responses through modulating the function of maturing DCs in inflamed tissues. However, no studies have directly addressed this question by co-culturing the two cell types in vitro. In this study, we utilized in vitro cultured human MCs, and examined the net effect of activated MCs as a whole on DCs. We found that (i) IgE-activated MCs induce DC maturation, as shown by the up-regulation of several surface molecules (Fig. 1), and potently suppress IL-12p70 production by DCs (Table 1), (ii) activated MCs alone do not have the ability to polarize DCs, but when combined with other DC maturation-inducing factors, such as LPS, TNF-{alpha}/IL-1ß (pro-inflammatory cytokines) or even LPS/IFN-{gamma} (potent IL-12-inducing factors), activated MCs induce DCs that suppress Th1 differentiation and promote Th2 differentiation (Fig. 3A–D) and (iii) histamine is an important mediator of these effects as reported (16–20), but a combinatorial effect of different MC-derived factors, including other soluble and cell contact-dependent factors, is required for the optimal induction of Th2-polarizing DCs (Fig. 3C and D).

There have been several MC-derived molecules reported to affect DC functions. First, histamine has been shown to up-regulate CD86 on DCs, suppress IL-12p70 production by DCs and polarize DCs toward a Th2-inducing type (16–20). In line with these reports, up-regulation of CD86 appeared to be almost totally dependent on histamine (Fig. 2). However, the addition of histamine together with LPS/IFN-{gamma} or LPS only partially suppressed IL-12p70 production, compared with the stronger suppressive effect of activated MCs (Table 1). In addition, histamine receptor antagonists only partially reversed the suppression of IL-12p70 production by activated MCs. Accordingly, the Th2-promoting effect of histamine and the Th2-attenuating effect of histamine receptor antagonists in the DC–MC co-culture were also partial (Fig. 3C and D). These data indicate that histamine alone is not sufficient to reproduce the IL-12-suppressing and Th2-promoting effects of activated MCs.

PGD2 is another mediator synthesized by activated MCs (4–6). Stimulation of MoDCs with PGD2 has been shown to diminish IL-12p70 production and favors a Th2 response (21, 22). In our study, however, inhibition of PGD2 synthesis by indomethacin (a cyclo-oxygenase inhibitor) did not influence the MC-induced suppression of IL-12p70 production (Table 1) and Th2 polarization of DCs (data not shown), even when it was combined with histamine receptor antagonists. Thus, PGD2 is not likely to be involved in Th2 induction by MCs in our system.

As other potential MC-derived soluble factors inducing Th2-promoting DCs, we examined two recently reported cytokines, IL-25 and TSLP. It has been reported that IL-25 is produced by a murine in vitro cultured MCs (48), and is implicated in induction of Th2 responses (49, 50). However, we could not detect IL-25 mRNA expressions in the DC–MC co-culture at several time points within 24 h (data not shown). Human in vitro cultured MCs have been shown to express TSLP mRNA, and TSLP induces maturation and Th2 polarization of human myeloid CD11c+ DCs (23, 25). However, stimulation of MoDCs with TSLP did not affect their phenotypes, indicating that they do not express a receptor for TSLP, and moreover, addition of anti-TSLP-blocking antibody to the DC–MC co-culture did not diminish the induction of Th2 responses by the DCs (data not shown). Thus, it is unlikely that IL-25 or TSLP is involved in the induction of Th2-promoting DCs in our co-culture system.

Due to localization of DCs and MCs in anatomical proximity and high-level expressions of DC-attracting chemokines by IgE-activated MCs (12, 13), MCs may well have chances to directly contact with DCs in inflamed tissues. When DCs and MCs were co-cultured in direct contact, suppression of IL-12p70 production and Th2 polarization of DCs were maximal, whereas separation of DCs and MCs by a porous membrane diminished these effects (Table 1 and Fig. 3C and D). These data suggest the presence of membrane-associated molecules on the surface of activated MCs that exert these effects in cooperation with MC-derived soluble factors.

Interestingly, DCs exhibited Th1-suppressing as well as Th2-promoting capacities only when DCs were co-cultured with activated MCs in the presence of other exogenous pro-inflammatory factors (Fig. 3A), including strong Th1-inducing factors (LPS/IFN-{gamma}) (Fig. 3C). It has been shown that helminth antigens, which induce Th2 responses, more profoundly altered gene expressions in DCs when mixed with LPS than used alone (51). This and our observations suggest that cooperation of Th2-inducing factors with pro-inflammatory, or even Th1-inducing, factors results in a full-blown Th2 response. This is consistent with the observations in mice where LPS can promote Th2 responses (52, 53), and may explain exacerbation of allergic symptoms by superimposed bacterial infections (54). These findings may also give a warning to an anti-allergy vaccine strategy that attempts to treat allergies by deviating the immune response toward Th1 (55); simple application of Th1-inducing factors may not alleviate a Th2 response, but may rather exacerbate it.

Whereas IL-12 plays a dominant role in Th1 development, the absence of IL-12 does not appear to be sufficient for Th2 development (25, 56). Using different experimental systems, several molecules inducing naive CD4+ T cells to differentiate into a Th2 type have been reported to be expressed by DCs (57). OX40L (25, 58–62) is one of the candidates of such Th2-inducing molecules. Moreover, Amsen et al. (63) demonstrated in a murine system that different Notch ligands on antigen-presenting cells instruct naive T cells to differentiate into different effector T cells; Delta promotes Th1 responses, while Jagged promotes Th2 responses, suggesting that DCs polarized by activated MCs may express high levels of Jagged. However, OX40L (Supplementary Fig. 1, available at International Immunology Online) was not detected on the Th2-inducing, LPS/IFN-{gamma}-stimulated DCs co-cultured with activated MCs by flow cytometry. In addition, there was no correlation between expression levels of Notch ligands (Jagged-1 and Jagged-2) measured by real-time reverse transcription–PCR and Th2-inducing capacity of DCs stimulated with different stimuli (Supplementary Fig. 2, available at International Immunology Online). These data indicate that neither OX40L nor Notch ligands are responsible for the Th2 polarization in our system.

de Jong et al. (64) demonstrated that Th1- or Th2-promoting DCs express diverse Th-polarizing signals according to types of microbial stimuli, and some Th2-promoting DCs exert its function via an OX40L-dependent mechanism, while others via an OX40L-independent, unknown mechanisms. Thus, Th2-inducing molecules on DCs may be diverse, depending on types of stimuli and DCs. It is possible that an unspecified Th2-inducing molecule, other than OX40L and Notch ligands, is expressed on Th2-promoting DCs co-cultured with activated MCs.

Finally, we examined anatomical relationships between DCs and MCs in inflammatory skin lesions. We chose biopsied specimens from patients with chronic atopic dermatitis, because we thought that DC–MC interactions would be most prominently visualized in Th2-type inflammatory lesions. In all specimens, both DCs and MCs were located in proximity in the dermis (Fig. 4). Intriguingly, MCs surrounded and entered the aggregates of DCs, suggesting production of MC-attracting chemokine by the DC aggregates, such as CCL5 and CCL8 (14) that can interact with CCR3 on MCs (15). These histological findings, together with the in vitro data that a relatively few MCs can influence T cell polarization induced by DCs (Fig. 3B), suggest that interactions of MCs with DCs are physiologically relevant in vivo, and that MCs may affect DC function through soluble and also possibly membrane-associated factors in the dermis of atopic lesions.

An IgE antibody is an end product of a Th2 response, and thus, IgE-mediated activation of MCs occurs as a consequence of a previous Th2 response. Our observation that IgE-activated MCs polarizes DCs toward Th2 implies that a DC–MC interaction may constitute a positive feedback loop to maintain or augment Th2 responses. Recently, Kalinski and Moser (65) proposed a ‘success-driven consensual immunity’ model, wherein outcomes of a ‘successful’ adaptive immune response induce polarization of DCs toward the same type of responses, constituting a positive feedback loop that stabilizes the type of adaptive immune responses. Our study is consistent with this model, demonstrating a successful Th2 response where IgE-activated MCs deliver signals to DCs results in the stabilization of the Th2 response. This mechanism may favor a defense against extracellular parasites by augmenting a Th2 response, but may also lead to persistence of unwanted Th2 responses, such as allergies. Thus, disruption of the DC–MC interaction may constitute an effective strategy to treat ongoing allergic reactions.


   Supplementary data
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Supplementary data
References
 
Supplementary figures are available at International Immunology Online.


   Acknowledgements
 
We thank Yoshinobu Toda (Center for Anatomical Studies, Graduate School of Medicine, Kyoto University) for excellent technical support in immunohistochemistry and Keiko Fukunaga for excellent technical assistance. This paper is supported in part by Establishment of International Center of Excellence (COE) for Integration of Transplantation Therapy and Regenerative Medicine (COE Program of the Ministry of Education, Culture, Science and Technology, Japan).


   Abbreviations
 
CD40L, CD40 ligand
COE, Center of Excellence
DC, dendritic cell
GM-CSF, granulocyte–macrophage colony-stimulating factor
MC, mast cell
MoDC, monocyte-derived dendritic cell
OX40L, OX40 ligand
PGD2, prostaglandin D2
PMA, phorbol myristate acetate
SCF, stem cell factor
TNF, tumor necrosis factor
TSLP, thymic stromal lymphopoietin

   Notes
 
Transmitting editor: G. Trinchieri

Received 16 March 2006, accepted 27 September 2006.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Supplementary data
 References
 

  1. Banchereau J, Briere F, Caux C, et al. (2000) Immunobiology of dendritic cells. Annu. Rev. Immunol. 18:767.[CrossRef][Web of Science][Medline]
  2. Kapsenberg ML. (2003) Dendritic-cell control of pathogen-driven T-cell polarization. Nat. Rev. Immunol. 3:984.[CrossRef][Web of Science][Medline]
  3. Kitamura Y. (1989) Heterogeneity of mast cells and phenotypic change between subpopulations. Annu. Rev. Immunol. 7:59.[Medline]
  4. Metcalfe DD, Baram D, Mekori YA. (1997) Mast cells. Physiol. Rev. 77:1033.[Abstract/Free Full Text]
  5. Marshall JS. (2004) Mast-cell responses to pathogens. Nat. Rev. Immunol. 4:787.[CrossRef][Web of Science][Medline]
  6. Galli SJ, Nakae S, Tsai M. (2005) Mast cells in the development of adaptive immune responses. Nat. Immunol. 6:135.[CrossRef][Web of Science][Medline]
  7. McLachlan JB, Hart JP, Pizzo SV, et al. (2003) Mast cell-derived tumor necrosis factor induces hypertrophy of draining lymph nodes during infection. Nat. Immunol. 4:1199.[CrossRef][Web of Science][Medline]
  8. Secor VH, Secor WE, Gutekunst CA, Brown MA. (2000) Mast cells are essential for early onset and severe disease in a murine model of multiple sclerosis. J. Exp. Med. 191:813.[Abstract/Free Full Text]
  9. Tanzola MB, Robbie-Ryan M, Gutekunst CA, Brown MA. (2003) Mast cells exert effects outside the central nervous system to influence experimental allergic encephalomyelitis disease course. J. Immunol. 171:4385.[Abstract/Free Full Text]
  10. Wang HW, Tedla N, Lloyd AR, Wakefield D, McNeil PH. (1998) Mast cell activation and migration to lymph nodes during induction of an immune response in mice. J. Clin. Invest. 102:1617.[Web of Science][Medline]
  11. Kashiwakura J, Yokoi H, Saito H, Okayama Y. (2004) T cell proliferation by direct cross-talk between OX40 ligand on human mast cells and OX40 on human T cells: comparison of gene expression profiles between human tonsillar and lung-cultured mast cells. J. Immunol. 173:5247.[Abstract/Free Full Text]
  12. Sallusto F, Schaerli P, Loetscher P, et al. (1998) Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur. J. Immunol. 28:2760.[CrossRef][Web of Science][Medline]
  13. Nakajima T, Inagaki N, Tanaka H, et al. (2002) Marked increase in CC chemokine gene expression in both human and mouse mast cell transcriptomes following Fcepsilon receptor I cross-linking: an interspecies comparison. Blood 100:3861.[Abstract/Free Full Text]
  14. Sallusto F, Palermo B, Lenig D, et al. (1999) Distinct patterns and kinetics of chemokine production regulate dendritic cell function. Eur. J. Immunol. 29:1617.[CrossRef][Web of Science][Medline]
  15. Ochi H, De Jesus NH, Hsieh FH, Austen KF, Boyce JA. (2000) IL-4 and -5 prime human mast cells for different profiles of IgE-dependent cytokine production. Proc. Natl Acad. Sci. USA 97:10509.[Abstract/Free Full Text]
  16. Caron G, Delneste Y, Roelandts E, et al. (2001) Histamine induces CD86 expression and chemokine production by human immature dendritic cells. J. Immunol. 166:6000.[Abstract/Free Full Text]
  17. Caron G, Delneste Y, Roelandts E, et al. (2001) Histamine polarizes human dendritic cells into Th2 cell-promoting effector dendritic cells. J. Immunol. 167:3682.[Abstract/Free Full Text]
  18. Mazzoni A, Young HA, Spitzer JH, Visintin A, Segal DM. (2001) Histamine regulates cytokine production in maturing dendritic cells, resulting in altered T cell polarization. J. Clin. Invest. 108:1865.[CrossRef][Web of Science][Medline]
  19. Gutzmer R, Langer K, Lisewski M, et al. (2002) Expression and function of histamine receptors 1 and 2 on human monocyte-derived dendritic cells. J. Allergy Clin. Immunol. 109:524.[CrossRef][Web of Science][Medline]
  20. Idzko M, la Sala A, Ferrari D, et al. (2002) Expression and function of histamine receptors in human monocyte-derived dendritic cells. J. Allergy Clin. Immunol. 109:839.[CrossRef][Web of Science][Medline]
  21. Gosset P, Bureau F, Angeli V, et al. (2003) Prostaglandin D2 affects the maturation of human monocyte-derived dendritic cells: consequence on the polarization of naive Th cells. J. Immunol. 170:4943.[Abstract/Free Full Text]
  22. Gosset P, Pichavant M, Faveeuw C, et al. (2005) Prostaglandin D2 affects the differentiation and functions of human dendritic cells: impact on the T cell response. Eur. J. Immunol. 35:1491.[CrossRef][Web of Science][Medline]
  23. Soumelis V, Reche PA, Kanzler H, et al. (2002) Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat. Immunol. 3:673.[Web of Science][Medline]
  24. Gilliet M, Soumelis V, Watanabe N, et al. (2003) Human dendritic cells activated by TSLP and CD40L induce proallergic cytotoxic T cells. J. Exp. Med. 197:1059.[Abstract/Free Full Text]
  25. Ito T, Wang YH, Duramad O, et al. (2005) TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J. Exp. Med. 202:1213.[Abstract/Free Full Text]
  26. Skokos D, Botros HG, Demeure C, et al. (2003) Mast cell-derived exosomes induce phenotypic and functional maturation of dendritic cells and elicit specific immune responses in vivo. J. Immunol. 170:3037.[Abstract/Free Full Text]
  27. Nakahata T, Tsuji K, Tanaka R, et al. (1995) Synergy of stem cell factor and other cytokines in mast cell development. In Kitamura Y, Yamamoto S, Galli SJ (Eds.). Biological and Molecular Aspect of Mast Cell and Basophil Differentiation and Function(Raven Press, New York) pp. 13.
  28. Yanagida M, Fukamachi H, Ohgami K, et al. (1995) Effects of T-helper 2-type cytokines, interleukin-3 (IL-3), IL-4, IL-5, and IL-6 on the survival of cultured human mast cells. Blood 86:3705.[Abstract/Free Full Text]
  29. Toru H, Ra C, Nonoyama S, Suzuki K, Yata J, Nakahata T. (1996) Induction of the high-affinity IgE receptor (Fc epsilon RI) on human mast cells by IL-4. Int. Immunol. 8:1367.[Abstract/Free Full Text]
  30. Toru H, Eguchi M, Matsumoto R, Yanagida M, Yata J, Nakahata T. (1998) Interleukin-4 promotes the development of tryptase and chymase double-positive human mast cells accompanied by cell maturation. Blood 91:187.[Abstract/Free Full Text]
  31. Yamaguchi M, Sayama K, Yano K, et al. (1999) IgE enhances Fc epsilon receptor I expression and IgE-dependent release of histamine and lipid mediators from human umbilical cord blood-derived mast cells: synergistic effect of IL-4 and IgE on human mast cell Fc epsilon receptor I expression and mediator release. J. Immunol. 162:5455.[Abstract/Free Full Text]
  32. Hsieh FH, Lam BK, Penrose JF, Austen KF, Boyce JA. (2001) T helper cell type 2 cytokines coordinately regulate immunoglobulin E-dependent cysteinyl leukotriene production by human cord blood-derived mast cells: profound induction of leukotriene C(4) synthase expression by interleukin 4. J. Exp. Med. 193:123.[Abstract/Free Full Text]
  33. Obata T, Nagakura T, Kanbe M, Masaki T, Maekawa K, Yamashita K. (1996) IgE-anti-IgE-induced prostaglandin D2 release from cultured human mast cells. Biochem. Biophys. Res. Commun. 225:1015.[CrossRef][Web of Science][Medline]
  34. Hough LB. (2001) Genomics meets histamine receptors: new subtypes, new receptors. Mol. Pharmacol. 59:415.[Free Full Text]
  35. Rissoan MC, Soumelis V, Kadowaki N, et al. (1999) Reciprocal control of T helper cell and dendritic cell differentiation. Science 283:1183.[Abstract/Free Full Text]
  36. Imura A, Hori T, Imada K, et al. (1996) The human OX40/gp34 system directly mediates adhesion of activated T cells to vascular endothelial cells. J. Exp. Med. 183:2185.[Abstract/Free Full Text]
  37. Toda Y, Kono K, Abiru H, et al. (1999) Application of tyramide signal amplification system to immunohistochemistry: a potent method to localize antigens that are not detectable by ordinary method. Pathol. Int. 49:479.[CrossRef][Web of Science][Medline]
  38. Bischoff SC and Dahinden CA. (1992) c-kit ligand: a unique potentiator of mediator release by human lung mast cells. J. Exp. Med. 175:237.[Abstract/Free Full Text]
  39. Bischoff SC, Sellge G, Lorentz A, Sebald W, Raab R, Manns MP. (1999) IL-4 enhances proliferation and mediator release in mature human mast cells. Proc. Natl Acad. Sci. USA 96:8080.[Abstract/Free Full Text]
  40. Gutzmer R, Diestel C, Mommert S, et al. (2005) Histamine H4 receptor stimulation suppresses IL-12p70 production and mediates chemotaxis in human monocyte-derived dendritic cells. J. Immunol. 174:5224.[Abstract/Free Full Text]
  41. Trinchieri G. (2003) Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat. Rev. Immunol. 3:133.[CrossRef][Web of Science][Medline]
  42. Hilkens CM, Kalinski P, de Boer M, Kapsenberg ML. (1997) Human dendritic cells require exogenous interleukin-12-inducing factors to direct the development of naive T-helper cells toward the Th1 phenotype. Blood 90:1920.[Abstract/Free Full Text]
  43. Snijders A, Kalinski P, Hilkens CM, Kapsenberg ML. (1998) High-level IL-12 production by human dendritic cells requires two signals. Int. Immunol. 10:1593.[Abstract/Free Full Text]
  44. Jutel M, Watanabe T, Klunker S, et al. (2001) Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors. Nature 413:420.[CrossRef][Medline]
  45. Mosialos G, Yamashiro S, Baughman RW, et al. (1994) Epstein-Barr virus infection induces expression in B lymphocytes of a novel gene encoding an evolutionarily conserved 55-kilodalton actin-bundling protein. J. Virol. 68:7320.[Abstract/Free Full Text]
  46. Mosialos G, Birkenbach M, Ayehunie S, et al. (1996) Circulating human dendritic cells differentially express high levels of a 55-kd actin-bundling protein. Am. J. Pathol. 148:593.[Abstract]
  47. Pinkus GS, Pinkus JL, Langhoff E, et al. (1997) Fascin, a sensitive new marker for Reed-Sternberg cells of Hodgkin's disease. Evidence for a dendritic or B cell derivation? Am. J. Pathol. 150:543.[Abstract]
  48. Ikeda K, Nakajima H, Suzuki K, et al. (2003) Mast cells produce interleukin-25 upon Fc epsilon RI-mediated activation. Blood 101:3594.[Abstract/Free Full Text]
  49. Fort MM, Cheung J, Yen D, et al. (2001) IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 15:985.[CrossRef][Web of Science][Medline]
  50. Kim MR, Manoukian R, Yeh R, et al. (2002) Transgenic overexpression of human IL-17E results in eosinophilia, B-lymphocyte hyperplasia, and altered antibody production. Blood 100:2330.[Abstract/Free Full Text]
  51. Kane CM, Cervi L, Sun J, et al. (2004) Helminth antigens modulate TLR-initiated dendritic cell activation. J. Immunol. 173:7454.[Abstract/Free Full Text]
  52. Kaisho T, Hoshino K, Iwabe T, Takeuchi O, Yasui T, Akira S. (2002) Endotoxin can induce MyD88-deficient dendritic cells to support T(h)2 cell differentiation. Int. Immunol. 14:695.[Abstract/Free Full Text]
  53. Piggott DA, Eisenbarth SC, Xu L, et al. (2005) MyD88-dependent induction of allergic Th2 responses to intranasal antigen. J. Clin. Invest. 115:459.[CrossRef][Web of Science][Medline]
  54. Kamradt T, Goggel R, Erb KJ. (2005) Induction, exacerbation and inhibition of allergic and autoimmune diseases by infection. Trends Immunol. 26:260.[CrossRef][Web of Science][Medline]
  55. Wohlleben G and Erb KJ. (2001) Atopic disorders: a vaccine around the corner? Trends Immunol. 22:618.[CrossRef][Web of Science][Medline]
  56. Jankovic D, Kullberg MC, Hieny S, Caspar P, Collazo CM, Sher A. (2002) In the absence of IL-12, CD4(+) T cell responses to intracellular pathogens fail to default to a Th2 pattern and are host protective in an IL-10(–/–) setting. Immunity 16:429.[CrossRef][Web of Science][Medline]
  57. Eisenbarth SC, Piggott DA, Bottomly K. (2003) The master regulators of allergic inflammation: dendritic cells in Th2 sensitization. Curr. Opin. Immunol. 15:620.[CrossRef][Web of Science][Medline]
  58. Ohshima Y, Yang LP, Uchiyama T, et al. (1998) OX40 costimulation enhances interleukin-4 (IL-4) expression at priming and promotes the differentiation of naive human CD4(+) T cells into high IL-4-producing effectors. Blood 92:3338.
  59. Chen AI, McAdam AJ, Buhlmann JE, et al. (1999) Ox40-ligand has a critical costimulatory role in dendritic cell: T cell interactions. Immunity 11:689.[CrossRef][Web of Science][Medline]
  60. Murata K, Ishii N, Takano H, et al. (2000) Impairment of antigen-presenting cell function in mice lacking expression of OX40 ligand. J. Exp. Med. 191:365.[Abstract/Free Full Text]
  61. Tanaka H, Demeure CE, Rubio M, Delespesse G, Sarfati M. (2000) Human monocyte-derived dendritic cells induce naive T cell differentiation into T helper cell type 2 (Th2) or Th1/Th2 effectors. Role of stimulator/responder ratio. J. Exp. Med. 192:405.[Abstract/Free Full Text]
  62. Ito T, Amakawa R, Inaba M, et al. (2004) Plasmacytoid dendritic cells regulate Th cell responses through OX40 ligand and type I IFNs. J. Immunol. 172:4253.[Abstract/Free Full Text]
  63. Amsen D, Blander JM, Lee GR, Tanigaki K, Honjo T, Flavell RA. (2004) Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 117:515.[CrossRef][Web of Science][Medline]
  64. de Jong EC, Vieira PL, Kalinski P, et al. (2002) Microbial compounds selectively induce Th1 cell-promoting or Th2 cell-promoting dendritic cells in vitro with diverse Th cell-polarizing signals. J. Immunol. 168:1704.[Abstract/Free Full Text]
  65. Kalinski P and Moser M. (2005) Consensual immunity: success-driven development of T-helper-1 and T-helper-2 responses. Nat. Rev. Immunol. 5:251.[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 BloodHome page
M. Hiasa, M. Abe, A. Nakano, A. Oda, H. Amou, S. Kido, K. Takeuchi, K. Kagawa, K. Yata, T. Hashimoto, et al.
GM-CSF and IL-4 induce dendritic cell differentiation and disrupt osteoclastogenesis through M-CSF receptor shedding by up-regulation of TNF-{alpha} converting enzyme (TACE)
Blood, November 12, 2009; 114(20): 4517 - 4526.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
T. Kambayashi, J. D. Baranski, R. G. Baker, T. Zou, E. J. Allenspach, J. E. Shoag, P. L. Jones, and G. A. Koretzky
Indirect involvement of allergen-captured mast cells in antigen presentation
Blood, February 1, 2008; 111(3): 1489 - 1496.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
A. L. Christy and M. A. Brown
The Multitasking Mast Cell: Positive and Negative Roles in the Progression of Autoimmunity
J. Immunol., September 1, 2007; 179(5): 2673 - 2679.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
18/12/1789    most recent
dxl113v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (10)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Kitawaki, T.
Right arrow Articles by Uchiyama, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kitawaki, T.
Right arrow Articles by Uchiyama, T.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?