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The Journal of Immunology, 2007, 179, 3425 -3433
Copyright © 2007 by The American Association of Immunologists, Inc.
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Histamine Improves Antigen Uptake and Cross-Presentation by Dendritic Cells1

Maria Marta Amaral*, Carlos Davio{dagger}, Ana Ceballos*, Gabriela Salamone*, Cristian Cañones*, Jorge Geffner* and Mónica Vermeulen2,*

* Institute of Hematologic Research, National Academy of Medicine and National Reference Center for AIDS, Department of Microbiology, Buenos Aires University School of Medicine, Buenos Aires, Argentina; and {dagger} Laboratory of Radioisotopes, Buenos Aires University School of Pharmacology and Biochemestry, Buenos Aires, Argentina


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
Previous studies have shown that histamine is able to modulate the function of dendritic cells (DCs). Histamine seems to be required for the normal differentiation of DCs. Moreover, it is capable of stimulating the chemotaxis of immature DCs and of promoting the differentiation of T CD4+ cells into a Th2 profile. In this study, we analyzed whether histamine was able to modulate endocytosis and cross-presentation mediated by immature DCs. Our results show that both functions are stimulated by histamine. Endocytosis of soluble HRP and FITC-OVA and cross-presentation of soluble OVA were markedly increased by histamine. Interestingly, stimulation of endocytosis and cross-presentation appeared to be mediated through different histamine receptors. In fact, the enhancement of endocytosis was prevented by the histamine2 receptor (H2R) antagonist cimetidine, whereas the stimulation of cross-presentation was prevented by the H3R/H4R antagonist thioperamide. Of note, contrasting with the observations made with soluble Ags, we found that histamine did not increase either the uptake of OVA-attached to latex beads, or the cross-presentation of OVA immobilized on latex beads. This suggests that the ability of histamine to increase endocytosis and cross-presentation is dependent on the Ag form and/or the mechanisms through which the Ag is internalized by DCs. Our results support that histamine may favor cross-presentation of soluble allergens by DCs enabling the activation of allergen-specific T CD8+ cells, which appears to play an important role in the development of allergic responses in the airway.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
Dendritic cells (DCs)3 are highly specialized APCs found in almost all peripheral tissues as well as in primary and secondary lymphoid organs (1, 2). They have the unique ability to activate resting T lymphocytes and play a critical role not only in the priming of adaptive immune responses, but also in the induction of self-tolerance (3, 4). Upon encountering inflammatory stimuli or pathogens in the periphery, DCs become activated and undergo a number of changes, leading to their terminal differentiation or maturation. These changes enable DCs to activate T cells and to direct the differentiation of CD4+ T cells into distinct profiles (5, 6, 7).

Studies on the mechanisms involved in the regulation of DC activity are mostly restricted to cytokines, chemokines, and microbial products. However, DCs are also able to recognize a large variety of stressors generated or released during the course of dangerous processes, including protons (8), angiotensin-II (9), bradikinin (10), the complement anaphylotoxin C5a (11), oxidants (12), and histamine (13). Histamine (2-[4-imidazole]-ethylamine) is a low m.w. amine synthesized by decarboxylation of histidine by the enzyme L-histidine decarboxylase (14). Mast cells and basophils are the major sources of histamine, whereas certain leukocyte populations such as neutrophils (15), macrophages (16), and T lymphocytes (17) do not store histamine, but are capable of producing and releasing high amounts of histamine. Histamine plays an important role in a variety of processes, such as neurotransmission, gastrointestinal and circulatory functions, and inflammatory responses responsible for allergic reactions (14, 18). More recent studies have shown that histamine is also able to modulate the function of DCs. Histamine appears to be involved in the normal differentiation of human DCs (19), and it is also capable of inducing the chemotaxis of immature DCs (20) and promoting the differentiation of T CD4+ cells into a Th2 profile (21, 22), a mechanism that seems to contribute to the severity of atopic diseases.

Recently, it has been shown that the development of airway hyperresponsiveness and lung inflammation in experimental models as well as in patients with asthma is dependent, not only on CD4+ Th2 cells, but also on CD8+ T cells (23, 24). These cells show a TC2 phenotype; produce IL-4, IL-5, and IL-13; and express the high-affinity receptor for leukotriene B4. This receptor appears to play an important role in the recruitment of allergen-specific CD8+ T cells in the lung (25).

Because APCs commonly find allergens in the extracellular space, the participation of T CD8+ cells in allergic reactions opens the question of how allergens could be routed for presentation on MHC class I molecules. In this study, we show that histamine stimulates both the uptake and the presentation of Ags by MHC class I molecules (cross-presentation), supporting a novel mechanism through which histamine may exacerbate the course of allergic reactions.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Disclosures
 References
 
Mice

All experiments were conducted using 2-mo-old virgin female C57BL/6 mice raised at the National Academy of Medicine (Buenos Aires, Argentina). They were housed six per cage and kept at 20 ± 2°C under automatic 12-h light-dark schedule. Animal care was in accordance with institutional guidelines.

Reagents

HRP, OVA, wortmannin, cytochalasin B, and mannan from Saccharomyces cerevisiae were from Sigma-Aldrich. RPMI 1640, FCS, penicillin, and streptomycin were from Invitrogen Life Technologies; histamine base, ketotifene (histamine1 receptor (H1R) antagonist), cimetidine (H2R antagonist), thioperamide maleate salt (H3R/H4R antagonist), and LPS from Escherichia coli 0111:B4 were from Sigma-Aldrich. The 257–264 OVA peptide (SIINFEKL) was provided by S. Amigorena (Institut Curie, Paris, France).

DC generation from bone marrow cultures

The procedure used in this study was described by Inaba et al. (26), with minor modifications (8). Briefly, bone marrow was flushed from the long bones of the limbs using 2 ml of RPMI 1640 with a syringe and 25-gauge needle. Red cells were lysed with ammonium chloride. After washing, cells were suspended at a concentration of 1.5 x 106 cells/ml in 70% RPMI 1640 medium supplemented with 10% FCS, 5.5 x 10–5 2-ME (Sigma-Aldrich) (complete medium), and 30% J588-GM cell line supernatant. The cultures were fed every 2 days by gently swirling the plates, aspirating 50% of the medium, and adding back fresh medium with J588-GM cell line supernatant. At day 9 of the culture, >90% of the harvested cells expressed MHC class II, CD40, and CD11c, but not Gr-1 (data not shown).

Conjugation of OVA to latex beads

A total of 200 µg/ml FITC-OVA or OVA was coupled to the surface of 3-µm carboxylated polystyrene (latex) beads by passive absorption, according to the manufacturer’s instructions (Polysciences), followed by extensive washing.

Endocytosis of FITC-OVA

Cells were suspended at 1.5 x 106/ml in complete medium. FITC-OVA was added at a final concentration of 100 µg/ml, and cells were incubated for 30 min at 37°C. Cells were then washed three times with cold PBS containing 1% FCS and 0.01% NaN3 and were analyzed using a FACS flow cytometer and CellQuest software (BD Biosciences). The fluorescence background (cells incubated with FITC-OVA at 4°C) was always subtracted. In some experiments, we used the dye trypan blue to quench extracellular fluorescence, as described (8, 27). Endocytosis assays were performed, as previously indicated, but acquisition of samples was conducted in the presence of 200 µg/ml trypan blue. The efficacy of trypan blue to quench extracellular fluorescence was controlled in experiments in which DCs were stained with FITC mAb directed to cell surface Ags (30 min at 4°C). In all cases, we observed that fluorescence intensity was diminished by >85% when the acquisition of the samples was performed in the presence of trypan blue.

Endocytosis of HRP

Endocytosis of HRP was performed, as previously described (28). Briefly, DCs (1.5 x 106/ml) were suspended in complete medium. HRP was added at a final concentration of 150 µg/ml, and cells were cultured for 30 min at 37°C. Then DCs were collected, washed four times in PBS containing 1% FCS and four times in cold PBS alone, and lysed with 0.05% Triton X-100 in 10 mM Tris buffer (pH 7.4) for 30 min, and the enzyme activity of the lysate was measured using o-phenylenediamine and H2O2 as substrates with reference to a standard curve, at 492 nm. The amount of HRP taken up by DCs was determined as the difference between HRP activities in disrupted and nondisrupted cells. HRP activity in nondisrupted DCs was always <15% compared with disrupted cells.

Phagocytosis of FITC-OVA-coated latex beads

A total of 1 x 106/ml DCs in 200 µl of complete culture medium was incubated with 50 µl of FITC-OVA-coated latex beads (109 beads/ml) for 3 h at 37°C. The uptake of FITC-OVA-coated latex beads was quantified by flow cytometry. Acquisition of the samples was performed in the presence of trypan blue (200 µg/ml) to quench extracellular fluorescence.

Analysis of the phenotype of DCs

Cell staining was performed using the following mAbs: anti-CD11c FITC, anti-CD40 FITC, anti-CD86 FITC, anti-I-Ab PE (MHC class II), anti-CD11b PE, anti-GR-1 PE, and anti-H-2Kb (MHC class I) (BD Pharmingen). Cell surface Ag expression was evaluated by single staining, and analysis was performed using a FACS flow cytometer and CellQuest software (BD Biosciences).

Radioligand-binding assays for the expression of H1R and H2R

[3H]Mepyramine-binding assay. Duplicate assays were performed in polyethylene tubes in 50 mM Tris-HCl (pH 7.4), as previously described (29). For saturation studies, increasing concentrations of [3H]mepyramine, ranging from 0.01 to 15 nM, were incubated with 106 cells/tube, in the absence or presence of 10 µM mepyramine, in a total volume of 100 µl. After 40 min at 4°C, incubation was stopped by dilution with 3 ml of ice-cold 50 mM Tris-HCl (pH 7.4) and rapid filtration under reduced pressure onto Whatman GF/B glass-fiber filters, followed by three washes with 3 ml of ice-cold buffer. Experiments were conducted at 4°C to avoid internalization of the ligand.

[3H]Tiotidine-binding assay. Duplicate assays were performed, as previously described (30), in polyethylene tubes in 50 mM Tris-HCl (pH 7.4). For saturation studies, increasing concentrations of [3H]tiotidine, ranging from 0.4 to 130 nM, were incubated with 106 cells/tube, in the absence or presence of 10 µM tiotidine, in a total volume of 100 µl. After 40 min at 4°C, incubation was stopped by dilution with 3 ml of ice-cold 50 mM Tris-HCl (pH 7.4) and rapid filtration under reduced pressure onto Whatman GF/B glass-fiber filters, followed by three washes with 3 ml of ice-cold buffer. Experiments were conducted at 4°C.

In all cases, specific binding was calculated by subtraction of nonspecific from total binding. Analysis of radioligand-binding data was done using GraphPad Prism 3.00 for Windows. One-way ANOVA with Dunnett’s posttest was performed using GraphPad InStat version 3.01.

Analysis of the expression of H3R and H4R by RT-PCR

Total RNA was extracted from brain (positive control for H3R), bone marrow (positive control for H4R), and mouse DCs, using TRIzol reagent (Invitrogen Life Technologies). The reverse-transcription reaction contained 3 µg of total RNA, and it was performed using the M-MLV reverse-transcriptase enzyme (Promega). The primers were provided by Invitrogen Life Technologies. Forward primers for the H3R and H4R are as follows: TAC AAG GGC CTG GCC GTA GAA GG and CGT GTT GTT TAA CTG GAA TTT TGG AAG TGG AAT CTG CAT G, respectively. Reverse primers for the H3R and H4R are as follows: GCT GTC GCG GGA CAA GAA GG and ACC AAG AAA GCC AGT ATC CAA ACA GCC ACC ATT TGA GC, respectively. A GeneAmp PCR system (PerkinElmer/Applied Biosystems) was used. PCR products were separated on a 1.5% agarose gel, stained with ethidium bromide, and visualized by an UV transilluminator.

Histamine production

It was measured in cell supernatants using a commercial histamine ELISA kit (IBL).

Quantification of cellular apoptosis and viability by fluorescence microscopy

Quantification was conducted, as described (31), using the fluorescent DNA-binding dyes acridine orange (100 µg/ml), to determine the percentage of cells that had undergone apoptosis, and ethidium bromide (100 µg/ml), to differentiate between viable and nonviable cells. With this method, nonapoptotic cell nuclei show structure, variations in fluorescence intensity that reflect the distribution of euchromatin and heterochromatin. By contrast, apoptotic nuclei exhibit highly condensed chromatin that is uniformly stained by acridine orange. In fact, the entire apoptotic nucleus is present as bright spherical beads. To assess the percentage of cells showing morphologic features of apoptosis, at least 200 cells were scored in each experiment.

Ag cross-presentation assay

Presentation of OVA epitope 257–264 on Kb was detected using the T cell hybridoma B3Z, which carries a beta-galactosidase construct driven by NF-AT elements from the IL-2 promoter (8). For Ag presentation assays, DCs were exposed to different concentrations of soluble OVA or OVA-coated latex beads (DC:bead ratio: 1:50) during 3 h at 37°C. Then cells were washed, suspended in complete medium, and cultured in the presence of the T cell hybridoma B3Z. After 18 h of culture, cells were washed with PBS, and a colorimetric assay using o-nitrophenyl-p-D-galactoside (ONPG) (Sigma-Aldrich) as a substrate was used to detect LacZ activity in B3Z lysates. Pulse-chase experiments were conducted by incubating DCs with soluble OVA for 3 h at 37°C. Cells were then washed and cultured for various chase periods, after which B3Z cells were added and cross-presentation was assessed, as described above.

Statistical analysis

The significance between means was assessed by Student’s t test. Value of p < 0.05 was taken as indicating statistical significance.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Disclosures
 References
 
DCs express the four subtypes of HR

Histamine exerts its (patho)physiological effects through the interaction with four receptor subtypes (HR) that all belong to the family of G protein-coupled receptors (32, 33, 34). Using Western blot analysis or RT-PCR, previous studies have shown that murine DCs express H1R and H2R (35). To gain insight into the properties of these receptors in DCs, we analyzed their expression using a radioligand-binding assay conducted with specific ligands for H1R and H2R, [3H]mepyramine, and [3H]tiotidine, respectively. Fig. 1, A and B, shows that both, H1R and H2R express a single saturable binding site, being the number of sites almost 10-fold higher for H1R compared with H2R. Values for Kd were 1.1 ± 0.1 nM and 10 ± 0.8 nM, for H1R and H2R, respectively. Moreover, because no previous studies have demonstrated the expression of H3R and H4R in murine DCs, we analyzed this point by using RT-PCR. Fig. 1, C and D, shows that RT-PCR amplification yielded DNA fragments for the expected size for both H3R and H4R.


Figure 1
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  		FIGURE 1. DCs express the four HR. A and B, Receptor-binding assays were performed using [3H]mepyramine and [3H]tiotidine as radioligands for H1R and H2R, respectively. The results are expressed as bound (sites/cell) vs free (nM) of three experiments. C and D, RNAs from brain (H3R-positive control), bone marrow (H4R-positive control), and DCs were used to evaluate the expression of H3R and H4R.

 
Immune cells such as neutrophils (15), macrophages (16), as well as T lymphocytes (17) synthesize histamine. Fig. 2A shows that DCs also produce histamine. The amount of histamine in the supernatants of the cell cultures (1.5 x 106 DCs/ml) was in the range of 3.2–4.6 ng/ml. This concentration did not increase at longer periods of incubation, supporting that newly synthesized histamine is rapidly catabolized; however, as shown in Fig. 2B, activation by LPS resulted in a marked increase in the concentration of histamine in the supernatants of DC cultures.


Figure 2
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  		FIGURE 2. DCs constitutively produce histamine. A, DCs were washed, suspended at a concentration of 1.5 x 106/ml, and cultured for different periods. The presence of histamine in cell supernatants was evaluated by ELISA. A representative experiment is shown. B, Histamine production by DCs cultured for 30 min at 37°C in the absence or presence of LPS (10 ng/ml). Results are expressed as the mean ± SEM of four experiments. Asterisk represents the statistical significance (*, p < 0.05 for LPS vs controls).

 
Histamine stimulates endocytosis by DCs

Immature DCs have an extraordinary ability to sample the surrounding environment by endocytosis. They use two main mechanisms for Ag capture, as follows: macropinocytosis, which occurs in a constitutive fashion in DCs and allows continuous internalization of Ags present in the fluid phase, and receptor-mediated endocytosis, which involves the internalization of soluble Ags after clustering of receptors in clathrin-coated pits (36, 37). We analyzed whether histamine was able to modulate the endocytic capacity of immature DCs. To this aim, we used two endocytic markers, HRP and FITC-OVA. Fig. 3A shows that histamine markedly stimulated the uptake of HRP. This effect was almost completely prevented by mannan, supporting the involvement of the mannose receptor. The uptake of FITC-OVA was also increased by histamine (Fig. 3, B and C). To be sure that FITC-OVA was actually internalized by DCs and not merely attached to the cell surface, we performed additional assays in which endocytosis was conducted as described in Fig. 3B, but the acquisition of samples was performed in the presence of trypan blue (200 µg/ml), a dye capable of quenching extracellular fluorescence (8, 27). A marked stimulation of endocytosis was also observed under these conditions as follows: mean fluorescence intensity (MFI) = 27 ± 6 vs 65 ± 9, unstimulated vs 0.1 µM histamine-stimulated DCs, mean ± SEM, n = 5, p < 0.05. This supports that histamine actually stimulates endocytosis of FITC-OVA by DCs. Fig. 3C shows that mannan partially prevented the enhancement of FITC-OVA endocytosis induced by histamine supporting, in agreement with previous observations (38), the participation of the mannose receptor in the uptake of soluble OVA. However, macropinocytosis appeared to be also involved in the uptake of FITC-OVA by histamine-treated DCs. In fact, we observed that two inhibitors of macropinocytosis, the microfilament disrupting agent cytochalasin B and the inhibitor of PI3K wortmannin (39, 40, 41), markedly prevented the uptake of FITC-OVA (Fig. 3C).


Figure 3
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  		FIGURE 3. Histamine stimulates endocytosis of HRP and FITC-OVA by DCs. A, DCs (1.5 x 106/ml) were incubated with or without histamine (0.1 µM) for 30 min at 37°C, and then for 15 min in the absence or presence of mannan (MN, 1 mg/ml). Cells were then cultured with HRP (150 µg/ml) for 30 min at 37°C, and the uptake of HRP by DCs was determined by measuring HRP activity in cell lysates, as described in Materials and Methods. {square}, Represent the endogenous HRP-like activity of DCs that have not been fed with HRP. Results are expressed as OD at 492 nm and represent the arithmetic mean ± SEM of four to seven experiments. *, p < 0.05 for histamine vs controls; **, p < 0.05 for MN vs Ct, and histamine MN vs histamine (HIS). B, DCs (1.5 x 106/ml) were cultured for 30 min at 37°C with different concentrations of histamine. Then cells were incubated with OVA-FITC (100 µg/ml) for 1 h at 37°C, and endocytosis was measured by flow cytometry. Results are expressed as MFI values and represent the arithmetic mean ± SEM of eight experiments. *, p < 0.05 vs controls. C, DCs (1.5 x 106/ml) were incubated with or without mannan (1 mg/ml), wortmannin (200 nM), or cytochalasin (5 µg/ml) for 15 min at 37°C. Cells were incubated with ({blacksquare}) or without ({square}) histamine (0.1 µM) for 30 min at 37°C, and then OVA-FITC (100 µg/ml) was added. Endocytosis of OVA-FITC was measured after 1 h of incubation at 37°C by flow cytometry. Results are expressed as MFI and represent the arithmetic mean ± SEM of four to seven experiments. *, p < 0.05 for untreated vs histamine-treated DCs; **, p < 0.05 for untreated cells cultured with wortmannin or mannan vs control cells; ***, p < 0.05 for histamine-treated cells cultured with cytochalasin B, wortmannin, or mannan vs histamine-treated cells cultured in the absence of inhibitors. D, DCs (1.5 x 106/ml) were incubated with ketotifen, cimetidine, or thioperamide (100 µM) for 15 min at 37°C. Then cells were cultured for an additional period of 30 min at 37°C with ({blacksquare}) or without ({square}) histamine (0.1 µM), and endocytosis of FITC-OVA was evaluated by flow cytometry. Results are expressed as MFI and represent the arithmetic mean ± SEM of six to eight experiments. *, p < 0.05 for untreated vs histamine-treated DCs; **, p < 0.05 for histamine-treated cells cultured with cimetidine- vs histamine-treated cells cultured without cimetidine.

 
As expected, the maturation of DCs by LPS (10 ng/ml, 48 h) resulted in a dramatic inhibition of the endocytosis of FITC-OVA (100 µg/ml), which was not restored by treatment with histamine, as follows: MFI = 28 ± 5, 6 ± 2, and 8 ± 3, for immature DCs, LPS-maturated DCs, and LPS-maturated DCs treated with histamine (0.1 µM, 30 min at 37°C), respectively (mean ± SEM, n = 6).

To define the role of the different subtypes of HR in the stimulation of endocytosis by histamine, we used the specific receptor antagonists ketotifene (H1R), cimetidine (H2R), and thioperamide (H3R and H4R). Fig. 3D shows that the H2 antagonist cimetidine completely suppressed the stimulation of endocytosis by histamine, whereas the H1 and the H3/H4 antagonists, used at concentrations able to block the activity of these receptors in DCs (42, 43, 44), did not exert any effect. It should be noted that none of the antagonists used modified the endocytic ability of DCs when they were cultured in the absence of exogenous histamine, supporting that this function is not under the control of an autocrine loop involving histamine.

Histamine induces only minor effects on the phenotype and allostimulatory capacity of immature DCs

Contrasting results have been reported regarding the ability of histamine to induce the activation of DCs (13, 14, 34, 45). To re-examine this point, DCs were cultured for 18 h in the absence or presence of 0.1 µM histamine, and their phenotype was analyzed by flow cytometry. Fig. 4, A and B, shows that histamine induced a low, but significant increase in the expression of MHC class II, without modifying the expression of CD11c, CD40, and CD86. Similar results were observed using 1 µM histamine (data not shown). As shown in Fig. 4C, the enhanced expression of MHC class II induced by histamine correlated with the T cell-priming activity of DCs, as indicated by the ability of histamine to exert a low, but significant increase in the allostimulatory response mediated by DCs.


Figure 4
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  		FIGURE 4. Histamine increases MHC class II expression in DCs and improves their ability to induce MLR. A, DCs (1.5 x 106/ml) were cultured with or without histamine (0.1 µM) for 18 h at 37°C, and the phenotype was analyzed by flow cytometry. A, A representative experiment is shown. B, MHC class II expression was evaluated in DCs cultured for 18 h in the absence or presence of histamine (0.1 µM) or LPS (10 ng/ml). Results are expressed as the mean ± SEM of eight experiments. C, DCs (1.5 x 106/ml) were cultured with or without histamine (0.1 µM) or LPS (10 ng/ml) for 18 h at 37°C. Then DCs were washed and cocultured with freshly isolated allogeneic splenocytes for 5 days at two different ratios as follows: 1:10 and 1:20. Thymidine incorporation was measured on day 5 by a 16-h pulse with [3H]thymidine (1 µCi/well). Results are the mean ± SEM of five experiments. *, p < 0.05 vs controls.

 
Histamine stimulates cross-presentation by DCs

Cross-presentation is the process by which extracellular Ags, which are normally presented in association with MHC class II molecules, are instead routed for presentation on MHC class I molecules, enabling extracellular Ags to activate T CD8+ cells (4). This pathway is mainly mediated by DCs and can lead either to the tolerization or activation of Ag-specific CD8+ T cells (3, 46). Because allergen-specific T CD8+ cells appear to play an important role in the development of allergic reactions in the lung, and also considering that allergens are usually found at the extracellular space, we examined whether histamine may be able to stimulate Ag cross-presentation. This point was studied by analyzing the presentation of OVA to a CD8+ T cell hybridoma called B3Z, which carries a beta-galactosidase construct driven by NF-AT elements from the IL-2 promoter, enabling the analysis of T cell activation by measuring beta-galactosidase activity in cell lysates (8, 39). DCs were incubated with or without 0.1 µM histamine for 30 min at 37°C. They were then exposed to different concentrations of OVA during 3 h at 37°C, and presentation of the OVA257–264 epitope/H-2Kb to B3Z cells was assessed. Fig. 5A shows that histamine markedly improved MHC class I presentation. In fact, to allow similar levels of Ag presentation, untreated DCs required concentrations of Ag in the extracellular medium at least 10-fold higher compared with histamine-treated DCs. As expected, no Ag presentation was observed when DCs were fixed with glutaraldehyde before the addition of OVA (data not shown).


Figure 5
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  		FIGURE 5. Histamine stimulates cross-presentation of OVA by DCs. A, DCs (1.5 x 106/ml) were incubated with ({blacksquare}) or without ({square}) histamine (0.1 µM) for 30 min at 37°C. Then cells were incubated with different concentrations of OVA for 3 h at 37°C. DCs were washed and cultured for 18 h at 37°C with B3Z cells (1 x 106/ml), a T cell hybridoma specific for OVA-Kb, which carries a beta-galactosidase construct driven by NF-AT elements from the IL-2 promoter. T cell activation was measured using a colorimetric assay for LacZ activity with o-nitrophenyl-P-D-galactoside as a substrate. Background absorbance values obtained for DCs cultured in the absence of OVA were subtracted. *, p < 0.05 for histamine-treated cells vs controls. B, DCs (1.5 x 106/ml) were incubated with ketotifen, cimetidine, or thioperamide (100 µM) for 15 min at 37°C. Then cells were incubated with ({blacksquare}) or without ({square}) histamine (0.1 µM) for 30 min at 37°C. Cross-presentation of OVA was performed, as described above, using 2 µM OVA. *, p < 0.05 for histamine-treated cells cultured with thioperamide- vs histamine-treated cells cultured without thioperamide. C, DCs (1.5 x 106/ml) were incubated with or without thioperamide (100 µM) for 15 min at 37°C. Then different amounts of the 257–264 OVA peptide (SIINFEKL) were added. After 30 min at 37°C, the presentation of the peptide to B3Z cells was assessed. D, DCs (1.5 x 106/ml) were incubated with 2 µM OVA for 3 h at 37°C, washed, and incubated with or without histamine (0.1 µM) for 30 min at 37°C. Cross-presentation was then assessed, as described above. Results are expressed as OD at 492 nm and represent the arithmetic mean ± SEM of four to eight experiments. *, p < 0.05 vs controls.

 
Using the specific receptor antagonists ketotifene (H1R), cimetidine (H2R), and thioperamide (H3R and H4R), we then analyzed the role of HR in the stimulation of cross-presentation. Fig. 5B shows that ketotifene and cimetidine did not mediate any effect, whereas thioperamide completely abrogated the stimulation of cross-presentation by histamine. As shown in Fig. 5B, none of the antagonists assessed modulated cross-presentation of DCs cultured in the absence of histamine. To rule out any toxic effect mediated by thioperamide, we performed additional experiments in which the effect of thioperamide on the direct presentation of the OVA257–264 peptide to B3Z cells was analyzed. Fig. 5C shows that thioperamide did not disturb this process. Additional experiments were also performed to be sure that thioperamide treatment did not result in a loss of DC viability. To this aim, DCs were cultured with 100 µM thioperamide for 48 h, in the absence or presence of 0.1 µM histamine, and the percentages of cell viability were determined by fluorescence microscopy, as described in Materials and Methods. The percentages of cell viability were, in all cases, higher than 85%, whereas the percentages of apoptotic cells were lower than 12%. We also determined the absolute number of DCs recovered after 48 h of culture, and found that cell recovery was always higher than 80%. Together, these data indicate that thioperamide does not induce deleterious effects on DCs.

We then performed a new set of experiments directed to analyze the mechanisms involved in the stimulation of cross-presentation by histamine. First, we studied whether histamine was also able to stimulate cross-presentation when added after Ag pulsing. DCs were first cultured with OVA (2 µM) for 3 h at 37°C in the absence of histamine. Then cells were washed and cultured for an additional period of 30 min at 37°C with or without 0.1 µM histamine, in the absence of exogenous OVA. Cross-presentation was then assessed, as described in Fig. 5A. The results obtained (Fig. 5D) showed that histamine stimulated cross-presentation of OVA even when it was added to DC cultures after extracellular OVA was removed from the culture medium. We then analyzed whether histamine may be able to increase the expression of MHC class I molecules on DCs. No changes were observed in the expression of MHC class I in DCs cultured for 0.5, 2, 4, and 18 h in the presence of histamine (Fig. 6, A and B).


Figure 6
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  		FIGURE 6. Histamine does not increase the expression of MHC class I, but prolongs the expression of MHC class I-257–264 OVA peptide complexes in DCs pulsed with soluble OVA. A, DCs (1.5 x 106/ml) were cultured with or without histamine (0.1 µM) for 18 h at 37°C, and expression of MHC class I was analyzed by flow cytometry. A representative experiment is shown. B, DCs (1.5 x 106/ml) were cultured with (•) or without ({circ}) histamine (0.1 µM) for different periods at 37°C, and the expression of MHC class I was analyzed by flow cytometry. Results are expressed as MFI and represent the arithmetic mean ± SEM of three experiments. C, Pulse-chase experiments were performed by incubating histamine-pretreated (0.1 µM, 30 min at 37°C) or untreated DCs with or without OVA for 3 h at 37°C. OVA was then removed from the culture medium, and DCs were cultured for various chase periods, after which B3Z cells were added and cross-presentation was assessed, as described in Materials and Methods. A representative experiment (n = 3) is shown.

 
Additional studies were then performed to determine whether histamine may enable OVA-pulsed DCs to express the MCH-I peptide complexes for longer periods compared with control DCs. This point was analyzed using a functional assay in pulse-chase experiments. Histamine-pretreated or untreated DCs were cultured with OVA for 3 h at 37°C. OVA was then removed from the culture medium and DCs were cultured for various chase periods, after which B3Z cells were added and cross-presentation was assessed, as described above. Fig. 6C shows that the ability of untreated DCs to cross-present OVA declined after a chase period of 48 h. By contrast, the ability of histamine-treated DCs only declined after chase periods of 72–96 h.

It is well known that proteins internalized by either macropinocytosis or phagocytosis can be cross-presented (47, 48). To determine whether histamine was also able to enhance cross-presentation of Ags internalized by phagocytosis, experiments were performed using OVA-coated latex beads. As shown in Fig. 7A, and contrasting with the observations made with the soluble Ags HRP and FITC-OVA, histamine did not increase the uptake of FITC-OVA-coated latex beads, suggesting that it is unable to stimulate phagocytosis. Interestingly, Fig. 7B shows that histamine did not improve cross-presentation of OVA immobilized on latex beads, indicating that the ability of histamine to increase cross-presentation is strongly dependent on the Ag form and/or the mechanisms through which the Ag is internalized by DCs.


Figure 7
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  		FIGURE 7. Histamine does not stimulate phagocytosis nor cross-presentation of OVA immobilized on latex beads. A, DCs (1.5 x 106/ml) were cultured with (histograms B and D) or without 0.1 µM histamine (histograms A and C) for 30 min at 37°C, and phagocytosis of FITC-OVA-coated latex beads was performed, as described in Materials and Methods. A representative experiment is shown (n = 4). Histograms A and B, Cells incubated without FITC-OVA-coated latex beads. Histograms C and D, Cells incubated with FITC-OVA-coated latex beads. B, DCs (1.5 x 106/ml) were incubated without ({square}) or with ({blacksquare}) histamine (0.1 µM) for 30 min at 37°C. Then cells were incubated with OVA (2 µM) or OVA-coated latex beads, at a DC:bead ratio of 1:50, for 3 h at 37°C. DCs were then washed, and the cross-presentation assay was performed. Results are expressed as OD at 492 nm and represent the arithmetic mean ± SEM of three to five experiments. *, p < 0.05 vs controls.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Disclosures
 References
 
Histamine is an important mediator of immediate-type allergic reactions, and also modulates the function of DCs, the only APC capable of activating naive T lymphocytes (14). Previous studies directed to analyze the effect of histamine on DCs have mainly focused on the capacity of DCs to regulate the differentiation of T CD4+ cells into a Th1 or Th2 profile. Histamine has been shown to inhibit IL-12 and to increase IL-10 production by activated DCs, favoring the differentiation of T CD4+ cells into a Th2 profile (21, 49). This effect involves H2R and H4R and represents a positive feedback loop that seems to contribute to the severity of atopic diseases (20, 31, 50). It has also been demonstrated that histamine, acting through the H1R and H3R, induces the chemotaxis of immature DCs (45). Moreover, Szeberényi et al. (19) have shown that histamine is actively synthesized during the differentiation of DCs and that inhibition of histamine synthesis disturbs this process.

In the present study, we observed that immature DCs express the four subtypes of HR. Despite that in most systems H1R and H2R are able to mediate opposite effects (45, 51), no previous studies have examined the density and the affinity of these receptors in DCs. Using a radioligand-binding assay conducted with specific ligands for the H1R and H2R, we were able to define that each of these receptors expresses a single and saturable binding site of high affinity, and that the number of sites was almost 10-fold higher for H1R compared with H2R. Moreover, using RT-PCR, we found that DCs express not only the H4R, which is primarily expressed in the spleen, thymus, bone marrow, and peripheral blood leukocytes (14, 34, 52), but also the H3R, a receptor mainly expressed in the CNS (13, 33). We were unable, however, to validate the gene expression of H3R and H4R at the protein level by Western blot analysis because no specific Abs are available.

Immature DCs constitutively macropinocytose extracellular fluid (37), and also express a large variety of receptors mediating endocytosis and phagocytosis of Ags and pathogens (53). Our results show that histamine stimulates endocytosis by immature DCs. Because immature DCs and mast cells are strategically localized in close proximity at anatomic sites with high antigenic exposure such as skin and mucosal surfaces, we hypothesize that activation of endocytosis by histamine may be able to improve the Ag-sampling capacity of immature DCs in vivo. In this regard, it should be noted that concentrations of histamine similar to that used in our study (0.1 µM) were described in vivo at inflammatory sites during the course of allergic reactions (54, 55, 56).

In this study, we report, for the first time, that histamine is capable of stimulating cross-presentation of extracellular Ags. Cross-presentation enables DCs to present captured Ags through MHC class I molecules, thus providing a mechanism by which extracellular Ags could activate T CD8+ cell-mediated responses (44, 57). Interestingly, cross-presentation appears to play an important role, not only in antiviral and antitumor immunity, but also in the induction of tolerance (3, 58, 59). The ability of histamine to stimulate cross-presentation via H3R and/or H4R may represent a novel mechanism through which mast cells, the major cellular source of histamine, modulate the course of the adaptive immune response.

We have yet not defined the mechanisms through which histamine increases cross-presentation of soluble OVA. The enhancement of cross-presentation could not be merely explained by increased Ag uptake, because stimulation of cross-presentation and endocytosis appears to be mediated through distinct HR. Pulse-chase experiments, in contrast, suggested that histamine enables Ag-pulsed DCs to express MHC I-peptide complexes at the cell surface for longer periods. An enhanced expression of MHC I-peptide complexes as well as a more persistent expression of these complexes in Ag-pulsed DCs could be explained through different mechanisms, such as the facilitation of endosomal escape of the Ag to the cytosol or by changes in the mechanisms operating downstream this step. Of note, histamine was completely unable to increase cross-presentation of OVA bound to latex beads, used as a model of particulate Ag. It is well known that peptides derived from particulate Ags are cross-presented more efficiently than soluble Ags. This effect cannot be explained by increased Ag uptake, because cross-presentation of soluble Ags is enhanced by the addition of unrelated particles (47, 48), suggesting that phagocytosis itself favors Ag delivery into the MHC class I pathway. It has also been shown that particulate and soluble Ags use different transport pathways (47). Particulate Ags access to peripheral endoplasmic reticulum (ER)-like phagosomes, which are competent for cross-presentation, whereas soluble proteins may enter the lumen of the ER, being then translocated to the citosol. Finally, the generated peptides were transported back into the ER, where they bind to MHC class I molecules. We speculate that the ability of histamine to stimulate cross-presentation of soluble, but not particulate Ags could reflect an action exerted by histamine on the intracellular transport pathways specifically used by soluble, but not by particulate Ags. Interestingly, we also found that histamine efficiently stimulated the uptake of soluble, but not particulate Ags by DCs, supporting the view that the overall handling of soluble, but not particulate Ags by DCs might be under the regulation of histamine in peripheral tissues during the course of inflammatory allergic reactions.

It is now becoming clear that allergen-specific CD8+ T cells are important contributors to the development of allergic responses in the lung. They appear to be required for the development of both airway hyperresponsiveness and eosinophilic airway inflammation (23, 60). We hypothesize that stimulation of cross-presentation of allergens by DCs induced by histamine may be a novel mechanism through which mast cells contribute to the development of allergic responses via activation of allergen-specific T CD8+ cells.

Previous studies have shown that DCs produce histamine (19, 50). In fact, the intracellular levels of both histidine decarboxylase and histamine appear to increase during the differentiation of human monocytes into DCs (14, 52). Moreover, Dunford et al. (22) have reported the presence of histamine in cocultures of murine DCs and spleen T CD4+ cells, and also observed that the amounts of histamine in cell supernatants markedly increased as a consequence of LPS stimulation. Consistent with these results, we reported in this study that immature DCs constitutively produce histamine. However, the fact that neither the stimulation of endocytosis nor the promotion of cross-presentation was modulated by HR antagonists in DCs cultured in the absence of exogenous histamine supports that the autocrine production of histamine does not exert a modulatory effect on DC function under resting conditions. However, upon activation by LPS, the amount of histamine released by DCs markedly increased reaching 0.1 µM, a concentration able to increase endocytosis and cross-presentation by DCs (Figs. 3 and 5). This result supports the hypothesis that an autocrine loop involving histamine may modulate the function of DCs under inflammatory conditions.


   Acknowledgments
 
We thank Selma Tolosa and Evelia Lopez for their technical assistance, and Maria Rita Furnkorn for her secretarial assistance.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by grants from the Consejo Nacional de Investigaciones Científicas y Técnicas and Agencia Nacional de Promoción Científica y Tecnológica, Argentina. Back

2 Address correspondence and reprint requests to Dr. Mónica Vermeulen, Departamento de Inmunología, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Pacheco de Melo 3081, 1425 Buenos Aires, Argentina. E-mail address: mvermeulen{at}hematologia.anm.edu.ar Back

3 Abbreviations used in this paper: DC, dendritic cell; ER, endoplasmic reticulum; HR, histamine receptor; MFI, mean fluorescence intensity. Back

Received for publication December 18, 2006. Accepted for publication June 26, 2007.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 

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