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International Immunology Advance Access originally published online on November 21, 2006
International Immunology 2007 19(1):51-58; doi:10.1093/intimm/dxl121
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Increased antigen presentation and Th1 polarization in genetically histamine-free mice

Ivett Jelinek1, Valéria László1, Edit Buzás1, Éva Pállinger2, Balázs Hangya1, Zsuzsanna Horváth1 and András Falus1,2

1 Department of Genetics, Cell and Immunobiology, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary
2 Immunogenomics Research Group, Hungarian Academy of Sciences, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary

Correspondence to: V. László; E-mail: laszval{at}dgci.sote.hu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Histamine is a well-known inflammatory mediator exerting various immunomodulatory effects and affecting the development of antigen-specific immune responses. Dendritic cells (DCs) are the most potent antigen-presenting cells specialized for capture, uptake, transport, processing and presentation of antigens to T cells. Using a genetically histamine-free [histidine decarboxylase knockout (HDC–/–)] mouse model, we examined the effects of histamine on DC-mediated antigen presentation. Applying an in vitro antigen presentation assay, we found that spleen DCs, derived from HDC–/– mice, display a higher efficiency in antigen presentation compared with wild-type cells. Flow cytometric characterization of DCs disclosed that this difference was not due to an altered distribution of DCs between or within the major functional sub-populations (assessed by CD11b and CD4 as myeloid and CD8{alpha} and DEC205 as lymphoid DC markers) or major changes in the co-stimulatory molecule profile (CD40, CD80, CD86). However, real-time PCR analysis of in vivo CFA-induced IL-12p35, IFN{gamma}, IL-10 and IL-4 expression showed that DCs matured in a histamine-free environment exhibit significantly elevated levels of IL-12p35 and IFN{gamma} mRNA. In vitro investigations confirmed that isolated DCs, developed in the absence of histamine, exhibit indeed a predominantly Th1-polarized cytokine pattern, as they show elevated levels of IFN{gamma} mRNA upon LPS stimulation. Similar difference was found at the protein level by ELISA, as well. Our study demonstrates that histamine interferes with antigen presentation and alters the cytokine profile of DCs.

Keywords: antigen presentation, cytokine, dendritic cell, histamine, Th1 response


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Histamine—a well-known representative of biogenic amines—plays a pivotal role in various physiological and pathological processes in mammalian organisms. It is heavily involved in type I hypersensitivity reactions participating in vasodilatation, smooth muscle contraction, mucus hypersecretion and oedema formation (1, 2). Considering physiological processes, histamine is an important element of the regulatory system of hydrochloric acid secretion in the gastric mucosa (3, 4). In addition, it is secreted by well-defined populations of neurons (e.g. histaminergic neurons in the hypothalamic tuberomammillary nucleus), as neurotransmitter of the histaminergic pathways in the brain (5). Histamine also presents immunoregulatory properties as it modulates cytokine production of different cell types (e.g. mast cells, eosinophils) (6, 7). Histamine exerts its effects through four types of receptors: histamine H1R, H2R, H3R and the recently identified H4R (6). Regarding hematopoietic cells, a discrete set of cell types is able to secrete histamine, such as mast cells, basophils [participating in inflammation and allergic reactions (8)], eosinophils, and monocytes, and it was also detected in different types of dendritic cells (DCs) (9, 10), which are in the focus of our study.

DCs play important roles in the cellular immune response, being the most potent antigen-presenting cells (APCs). They take up and process antigens and present them to T lymphocytes with the help of MHC molecules, thus inducing tolerance to self-specific peptides or immunity against foreign antigens (11–15). Many studies confirmed that local environmental factors, like cytokines, chemokines and other inflammatory mediators such as histamine, have a strong impact on DC maturation as well as on their functions (9, 16). Moreover, DCs also have the ability to produce several cytokines and chemokines to co-ordinate ongoing immune responses.

Different subsets of DCs, i.e. lymphoid, myeloid, plasmacytoid and Langerhans cells (17, 18), are known to express a remarkably broad spectrum of histamine receptors (19–22). Furthermore, some findings showed that histamine has an influence on DC differentiation, as well (16, 23, 24).

In this study, an attempt was made to investigate the effect of histamine on DC functions measuring antigen presentation and cytokine production of isolated spleen-derived DCs of histidine decarboxylase knockout (HDC–/–) (25) and wild-type mice. In pilot studies, we found that spleen DCs express H1R, H2R and the newly discovered H4R, which is in line with the above literature data. Therefore, we believe that spleen-derived DCs are appropriate models for investigating the effects of histamine on the functional properties of DCs. As HDC is the only enzyme responsible for the biosynthesis of histamine, HDC–/– mice represent a unique experimental system for studying the effects of histamine in a totally histamine-free environment, in vivo.

Our findings demonstrate that the absence of histamine affects the antigen-presenting capacity and the cytokine profile of DCs.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Mice
Wild-type and HDC–/– (25) mice generated by eight back-crosses to BALB/c background were used for this study. For all experiments, female mice were maintained under specific pathogen-free conditions and used at 8–10 weeks of age. To avoid histamine uptake by feeding, mice were kept on histamine-free diet (Altromin GmbH, Heidenau, Germany) for 2 weeks before the experiments. HDC–/– mice displayed characteristics similar to those of wild-type littermates in all experiments conducted unless otherwise specified.

DC isolation
DCs were generated from isolated spleens after Collagenase D digestion (Roche Diagnostics, Mannheim, Germany); CD11c+ cells were obtained by immunomagnetic bead selection with CD11c-MACS beads (Miltenyi Biotec, Bergisch Gladbach, Germany). The purity was checked by flow cytometry and the ratio of DCs was found to be >90% in all experiments.

In vitro antigen presentation assay
DCs, isolated from pooled spleens (two spleens in a pool, isolated from a total of 10 animals per group), were co-cultured at a density of 103 cells per well for 24 h with the T cell hybridoma cell line 5/4E8 (104 cells per well) specific for the human aggrecan G peptide (26). The culture medium consisted of 200 µl DMEM supplemented with 10% heat-inactivated FCS (Invitrogen, GIBCO, Paisley, UK), 10 mM HEPES (Boehringer Mannheim GmbH, Mannheim, Germany), 50 µM 2-mercaptoethanol, 2 mM glutamine, 1% non-essential amino acids, 1% sodium pyruvate and 160 µg ml–1 gentamicin in the presence of human aggrecan G peptide (1 µg per well) (ATEGRVRVNSAYQDK) (kindly provided by Ferenc Hudecz, Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös Loránd University, Budapest, Hungary). Then the supernatants (100 µl per well) were assayed in a CTLL-2 proliferation assay (27). Briefly, 5 x 103 IL-2-dependent CTLL-2 T cells per well were cultured in triplicate wells with hybridoma supernatants for 72 h, and CTLL proliferation was measured by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay. Data were measured by multiwell ELISA reader (Labsystems, Helsinki, Finland) at 540 nm.

In vitro DC stimulation
Three pools of magnetic bead-separated spleen DCs, isolated from age-matched groups of wild-type and HDC–/– mice (n = 6 in each group), were cultured in 24-well plates at a density of 2 x 106 cells per well for 24 h in RPMI-1640, supplemented with 10% heat-inactivated FCS (Invitrogen, GIBCO), 160 µg ml–1 gentamicin, 10 mM HEPES (Boehringer Mannheim GmbH), 2 mM glutamine and 50 µM 2-mercaptoethanol. Then the cells were treated with 1 µg ml–1 LPS and 10–6 M histamine for further 24 h. At last, cells were processed for RNA isolation and subsequent real-time PCR analysis.

In vivo DC stimulation
Mice (10 animals in each group) were injected intra-peritoneally with either 0.2 ml PBS or 0.2 ml emulsion of CFA containing 0.1 mg of Mycobacterium tuberculosis H37 Ra. After 9 days of immunization, mice were killed and spleens were removed for DC isolation. Isolated spleen DCs were used for RNA preparation followed by real-time PCR analysis.

Reverse transcription and real-time PCR
Total RNA was isolated from both freshly isolated and in vitro cultivated spleen DCs using TRI reagent (Sigma–Aldrich, St Louis, MO, USA). After DNase I treatment, 2 µg total RNA per sample was reverse transcribed using random 6-mer primers and the Reverse Transcription System (all reagents from Promega Corp., Madison, WI, USA). Real-time PCR was performed by Taqman Universal PCR Mixes (Applied Biosystems, Foster City, CA, USA) on an AbiPrism® 7000 thermal cycler following the manufacturer's instructions. Taqman probe sets were used as follows: IL-12p35, IFN{gamma}, IL-10, IL-4, T-bet, GATA-3, histamine H1R, H2R, H3R and H4R and HGPRT as internal housekeeping control (all from Applied Biosystems).

Flow cytometry
To block unspecific antibody binding, magnetic bead-isolated DCs were incubated first with purified anti-mouse CD32/CD16 Mouse Fc Block (BD Biosciences PharMingen, San Diego, CA, USA), then stained with CD11c PE, I-A/I-E (MHCII) FITC, CD4 FITC, CD11b FITC, CD8{alpha} PerCP, DEC205 FITC, CD80 FITC, CD86 FITC and CD40 FITC antibodies (all from BD Biosciences PharMingen, except DEC205, Serotec Ltd, Oxford, UK). All flow cytometric analyses were performed using appropriate isotype controls (BD Biosciences PharMingen). Samples were analyzed by FACSCaliburTM flow cytometer and CellQuestTM software (BD Biosciences PharMingen).

ELISA
IFN{gamma} protein content of in vitro stimulated DC culture supernatants were assessed using a Quantikine Mouse IFN{gamma} Immunoassay Kit (R&D Systems, Minneapolis, MN, USA), following the manufacturer's instructions.

Statistics
Statistical analysis was done using two-way analysis of variance (ANOVA) or two-way repeated measures ANOVA, as appropriate, and Holm–Sidak test as post hoc test.

All the reagents, the origin of which was not specified, were purchased from Sigma–Aldrich.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
DCs derived from HDC–/– mice exhibit increased antigen-presenting capacity
DCs have been well documented to be the most potent APCs. They not only activate naive T cells but also determine the quality and efficacy of T cell response by distinct patterns of co-stimulatory signals and cytokine expression.

Therefore, we compared the antigen-specific T cell stimulation capacity of wild-type and HDC–/– DCs by an in vitro antigen presentation assay. DCs were cultured with aggrecan-specific 5/4E8 T cell hybridomas, and human aggrecan G peptide were added to the cultures for 24 h. Then antigen-specific IL-2 production of the T cell hybridomas was assayed in an IL-2-dependent CTLL-2 proliferation assay. Using this system, we were able to establish a very sensitive assay because as few as 103 DCs per well were able to effectively stimulate 104 5/4E8 T cells to produce easily detectable amounts of IL-2 (P < 0.001). In this assay, we found a remarkable difference in the antigen-presenting capacity of wild-type and HDC–/– DCs, as HDC–/– DCs stimulated T cells more effectively than their wild-type counterparts (P = 0.002, Fig. 1).


Figure 1
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  		Fig. 1 In vitro antigen presentation capacity of wild-type (WT) and HDC–/– DCs. DCs, isolated from WT and HDC–/– mice, were co-cultured with the 5/4E8 T cell hybridoma cell line and human aggrecan G peptide was added as specific antigen. Antigen-specific T cell response was determined by CTLL-2 proliferation measurement using MTT assay. Values shown are means ± SEMs of five independent experiments. Statistical significance was calculated by two-way repeated measures ANOVA (**P < 0.01, ***P < 0.001).

 
Flow cytometric comparison of wild-type and HDC–/– spleen DC sub-populations
A number of reports have shown (7, 28) that distinct DC sub-populations exhibit different abilities for Th response regulation. However, careful comparison of the relative abundance of these DC sub-populations in the spleens of wild-type and HDC–/– mice did not reveal any marked difference between them.

There was no difference between wild-type and HDC–/– mice either in the total number of spleen DCs (CD11c+, MHCII+ cells) or in their surface marker expression patterns typical for the lymphoid (CD8{alpha}+, DEC205+) and myeloid (CD11b+, CD4+) DC sub-populations (Fig. 2). Similarly, no difference was found in the surface expression of the predominant DC co-stimulatory molecules (CD80, CD86, CD40, Fig. 2).


Figure 2
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  		Fig. 2 Expression of cell-surface molecules on WT and HDC–/– DCs. Expression of CD11c and MHCII (A), CD40, CD80 and CD86 co-stimulatory molecules (B) and specific DC sub-population markers (C) on DCs isolated from WT and HDC–/– spleens. The data shown are representative results from at least three individual experiments. Proportions of positive cells and mean fluorescence intensity (MFI) are shown in percentages and MFI values, respectively. Dotted lines represent staining with an adequate isotype control.

 
Differential expression of cytokines by HDC–/– DCs in vitro
One of the major hallmarks of DCs is their potent capacity to activate naive T cells in an antigen-dependent manner. Naturally, cytokines have an essential role in this process not only in the polarization of T cells to Th1, Th2 or regulatory T cells but also in the regulation of the intensity of the adaptive immune response. Since there was no marked phenotypic difference found between DCs differentiated and matured with or without histamine, we studied whether an altered cytokine production stands behind the altered antigen-presenting capacity of the HDC–/– DCs.

In order to check this possibility, an in vitro system was used to measure the cytokines expressed by DCs in the presence or absence of histamine. Three DC pools from wild-type and HDC–/– mice (six spleens in each) were treated with LPS (1 µg ml–1) or histamine (10–6 M) alone or with both LPS and histamine for 24 h. Then, IL-12p35, IFN{gamma}, IL-4 and IL-10 mRNA levels were measured by real-time PCR. In contrast to IL-12p35, IL-10 and IFN{gamma}, which could be detected easily, the expression levels of IL-4 remained below the sensitivity of this technique (data not shown). In comparison with wild-type DCs, HDC–/– DCs displayed significantly higher levels of the typical Th1 cytokine IFN{gamma} (Fig. 3B), while no such difference was seen in the case of IL-12p35 and IL-10 (Fig. 3A and C). Both IFN{gamma} and IL-10, but not IL-12p35 were found to be elevated upon LPS stimulation (P = 0.001 and P = 0.004, respectively, Fig. 3). Interestingly, however, in vitro histamine administration failed to affect any of the cytokines investigated (Fig. 3).


Figure 3
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  		Fig. 3 Cytokine response of in vitro stimulated WT and HDC–/– DCs. DCs pooled from six animals were treated with LPS (1 µg ml–1) or histamine (H) (10–6 M) alone or with both LPS and H for 24 h, and the expression levels of IL-12p35 (A), IFN{gamma} (B) and IL-10 (C) were measured by real-time PCR. Values shown are means ± SEMs of three independent experiments. Statistical significance was calculated by two-way repeated measures ANOVA (*P < 0.05, **P < 0.01).

 
Finally, IFN{gamma} ELISA measurements were performed from the cell culture supernatants of in vitro activated DCs to check the reliability of the mRNA level observations. Statistical analysis of the collected data showed remarkable difference between the INF{gamma} expression levels of wild-type and HDC–/– DCs, the latter releasing significantly more IFN{gamma} (P = 0.007, Fig. 4). This is in line with the mRNA data and strongly supports our notion that HDC–/– DCs mediate stronger Th1-type signals than DCs matured in the presence of histamine.


Figure 4
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  		Fig. 4 INF{gamma} release of in vitro stimulated WT and HDC–/– DCs. DCs pooled from six animals were treated with LPS (1 µg ml–1) or histamine (H) (10–6 M) alone or with both LPS and H for 24 h, and the amount of IFN{gamma} protein, released in the cell culture supernatant, was determined by IFN{gamma} ELISA. Values shown are means ± SEMs of three independent experiments. Statistical significance was calculated by two-way repeated measures ANOVA (**P < 0.01, ***P < 0.001).

 
Stimulated HDC–/– DCs exhibit Th1-polarized cytokine profile in vivo
In order to confirm the above in vitro data, an in vivo approach was used to determine the effect of histamine on the cytokine expression capacity of DCs. In this experiment, we stimulated wild-type and HDC–/– mice with CFA in vivo and then we examined the expression of various Th1 and Th2 response-related genes. Our statistical analysis showed an obvious Th1 dominance in the cytokine profile of CFA-stimulated HDC–/– DCs (Fig. 5).


Figure 5
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  		Fig. 5 Cytokine responses of in vivo activated WT and HDC–/– DCs. WT and HDC–/– mice were injected with CFA, and after 9 days IL-12p35 (A), IFN{gamma} (B), IL-10 (C) and IL-4 (D) expression of isolated spleen DCs were measured by real-time PCR. Values shown are means ± SEMs of five independent experiments. Statistical significance was calculated by two-way ANOVA (*P < 0.05, **P < 0.01, ***P < 0.001).

 
The expression level of IL-12p35 was found to be substantially higher both in the unstimulated (P = 0.009) and CFA-stimulated HDC–/– DCs (P = 0.015), than in wild-type DCs. Remarkably, IL-12p35 levels remained unchanged upon CFA treatment, however (Fig. 5A). Furthermore, HDC–/– DCs produced higher amounts of IFN{gamma}, than the wild-type ones, significant difference, however, emerged only after stimulation with CFA (P = 0.023, Fig. 5B). With respect to IL-10, there was significant difference in the cytokine mRNA level of unstimulated wild-type and HDC–/– DCs, in as much as the latter produced significantly more IL-10 mRNA (P < 0.001). On the other hand, CFA treatment significantly decreased the expression of IL-10 in HDC–/– DCs (P = 0.008), while it had no significant effect on the wild type (Fig. 5C). Finally, IL-4 levels were the same in the two DC groups without stimulation, but IL-4 was suppressed by CFA in the wild-type animals stronger (P = 0.021), than in their HDC–/– littermates (Fig. 5D). Surprisingly, no significant difference was detected in the expression of the two main transcription factor associated with Th1 and Th2 polarization, T-bet and GATA-3, respectively (data not shown).

These findings suggest that the cytokine profile of stimulated DCs supports a predominantly Th1-type response in HDC–/– mice.

In addition to the cytokine profile analysis, we checked the possibility whether in vivo CFA stimulation was able to alter the histamine receptor expression patterns of DCs, thus implying the existence of an additional regulatory circuit of histamine signaling on DCs. We were able to detect H1R, H2R and H4R, but not H3R in splenic DCs. H4R was unaffected by either the treatment or the genotype. In contrast to that, both H1R and H2R were significantly up-regulated in unstimulated HDC–/– DCs (P < 0.001 and P = 0.002, respectively, Fig. 6A and B). Nevertheless, this difference was completely eliminated upon CFA treatment (Fig. 6A and B).


Figure 6
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  		Fig. 6 Histamine receptor expression of in vivo activated WT and HDC–/– DCs. WT and HDC–/– mice were injected with CFA, and after 9 days H1R (A), H2R (B) and H4R (C) expression patterns of purified splenic DCs were assessed by real-time PCR. Values shown are means ± SEMs of five independent experiments. Statistical significance was calculated by two-way ANOVA (**P < 0.01, ***P < 0.001).

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Histamine is well known about its different roles in the immune system (6, 7). In this study, we examined the possible effects of histamine on DCs, because DCs are the main APCs and it is highly probable that histamine (produced both by other cells and by DCs themselves) gets in close connection with DCs in the tissue environment. In this study, using a histamine-free, HDC–/– mouse model, we made an attempt to describe the effects of histamine-mediated signals on DC activity.

First, we provided evidence that DCs derived from HDC–/– mice exhibit higher antigen-presenting capacity, than the ones of the wild type. Basically, the efficiency of antigen presentation is influenced by many factors, such as the subtype of DCs, the mechanism of antigen uptake, the antigen processing and mainly the expression level of cell-surface co-stimulatory molecules. As we were unable to detect any alteration in the distribution of DCs between different DC subsets or regarding the expression of their most important co-stimulatory molecules, we focused our investigations on the cytokine profile of these DCs. Histamine has been shown to be involved in the regulation of the cytokine network (6, 7), and in accordance with these results, we were able to demonstrate that histamine has an important role in the regulation of the cytokine production by DCs. From our in vitro experiments, it became clear that histamine signaling is able to alter the cytokine production of DCs. Under in vitro conditions, DCs that differentiated in a histamine-free environment (in HDC–/– mice) responded with an enhanced cytokine production to LPS stimulation compared with control DCs that developed in the presence of histamine (in HDC+/+ mice). It seems that DCs that differentiated in vivo, in the absence of histamine, exhibit Th1-type cytokine dominance upon in vitro LPS stimulation as they produce more IFN{gamma} both at mRNA and protein levels. Apparently, however, in vitro histamine treatment of already differentiated DCs was not sufficient to recall these changes.

Knowing the limitations of in vitro systems and the highly different effects of various stimuli on DCs, we further checked these initial results applying an in vivo approach using another independent DC stimulator, CFA, as well. We found again that the lack of histamine resulted in Th1-type polarization of the DCs, as HDC–/– DCs expressed higher amounts of typically Th1-type cytokines like IL-12p35 and IFN{gamma} than their wild-type littermates.

Interestingly, IL-10, an anti-inflammatory, immunosuppressive, Th2-type cytokine, was found to be also up-regulated in the unstimulated, HDC–/– DCs. However, upon activation, HDC–/– mice were found to down-regulate the IL-10 production of their DCs, an effect which was not characteristic for the wild-type mice. Taken together, these data showed that DCs activated to antigen presentation display a rather Th1-polarized cytokine profile in HDC–/– mice.

Finally, we confirmed the presence of H1R, H2R and H4R mRNA and compared the intensity of their expression in wild-type and HDC–/– DCs. Our data show that the lack of histamine induces heavy disturbance in the expression of histamine H1R and H2R mRNA in DCs, as HDC–/– DCs massively over-expressed them. This data may be very interesting, but obviously do not provide any simple explanation for the observed Th1 polarization of HDC–/– DCs, because H1R and H2R seem to have opposite effects on Th1–Th2 polarization (29). In addition, this phenomenon was no more detectable after CFA stimulation, suggesting that this regulatory circuit may be strongly dependent on other environmental factors and may be abolished under certain circumstances, such as CFA stimulation.

To sum up, in this study we showed that histamine has a pivotal role in DC functions, but it appears to act rather indirectly, by reducing the production of Th1 cytokines in mature, antigen-presenting DCs. It is well known that both IL-12 and IFN{gamma}, produced by DCs, enhance antigen presentation by affecting several key components of the antigen presentation machinery, such as IFN{gamma}-inducible lysosomal thiol reductase (30), MHC class II transactivator (31) or the MHCII molecule itself (31), or by up-regulating several co-stimulatory molecules and stimulating DC maturation (32–34). As we detected increased expression of IL-12p35 and IFN{gamma} in the lack of histamine, this can be an explanation for the observed enhanced antigen presentation efficiency of HDC–/– DCs.

On the other hand, several groups have reported the existence of specialized DC groups with regulatory functions (35–37). These DC subsets produce large amounts of IL-10, polarize naive T cells into regulatory T cells and therefore inhibit the proliferation of activated T cells. It is also known that IL-10 has a direct inhibitory effect on the process of antigen presentation as well (38, 39). We demonstrated that the expression of IL-10 in stimulated HDC–/– DCs is strongly down-regulated after CFA stimulation and these could also contribute to the more effective immune response.

Taken together, we were able to demonstrate that histamine has a negative effect on the antigen presentation and the adaptive immune response by altering the cytokine profile of DCs. Further studies are needed to identify the sources, timing and tissue localization of histamine release responsive for the observed effects.


   Acknowledgements
 
Grateful acknowledgements are due to Zoltán Pós for his critical comments and useful help during the preparation of the manuscript of this article.


   Abbreviations
 
ANOVA, analysis of variance
APC, antigen-presenting cell
DC, dendritic cell
HDC–/–, histidine decarboxylase knockout

   Notes
 
Transmitting editor: I. Pecht

Received 3 January 2006, accepted 23 October 2006.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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A. Koncz, M. Pasztoi, M. Mazan, F. Fazakas, E. Buzas, A. Falus, and G. Nagy
Nitric Oxide Mediates T Cell Cytokine Production and Signal Transduction in Histidine Decarboxylase Knockout Mice
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