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© 2008 American Society for Nutrition J. Nutr. 138:544-550, March 2008

Nutritional Immunology

White Button Mushroom Enhances Maturation of Bone Marrow-Derived Dendritic Cells and Their Antigen Presenting Function in Mice1,2

Zhihong Ren, Zhuyan Guo, Simin Nikbin Meydani and Dayong Wu*

Nutritional Immunology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111

* To whom correspondence should be addressed: E-mail: dayong.wu{at}tufts.edu.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Mushrooms have been shown to enhance immune response, which contributes to their antitumor property. White button mushrooms (Agaricus bisporus) (WBM) constitute 90% of the total mushrooms consumed in the United States; however, the health benefit of this strain in general is not well studied. Furthermore, little is known about WBM's immunologic effects. Dendritic cells (DC) are the most potent antigen presenting cells and play a pivotal role in immune response by linking innate and adaptive immune responses. In this study, we investigated the effect of in vitro supplementation with WBM on maturation of bone marrow-derived DC (BMDC) of C57BL mice. BMDC were differentiated in the presence of whole mushroom concentrate at 50, 100, or 200 mg/L. Results showed that mushroom supplementation dose dependently increased the expression of maturation markers CD40, CD80, CD86, and major histocompatibility complex-II. Consistent with the changes in the phenotypic markers, functional assay for DC maturation showed that mushroom supplementation decreased DC endocytosis and increased intracellular interleukin (IL)-12 levels. Furthermore, using a syngeneic T cell activation model, we found that WBM-supplemented DC from BALB/c mice presented ovalbumin antigen to T cells from DO11.10 mice more efficiently as demonstrated by increased T cell proliferation and IL-2 production. In conclusion, WBM promote DC maturation and enhance their antigen-presenting function. This effect may have potential in enhancing both innate and T cell-mediated immunity leading to a more efficient surveillance and defense mechanism against microbial invasion and tumor development.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Medicinal use of mushrooms as folklore has a long history and studies in the last few decades have demonstrated that mushrooms and their constituting active components have beneficial effects on a variety of biological systems. One of the most cited health benefits of mushrooms is their anticancer property. Clinical and experimental studies thus far have suggested that mushrooms and their polysaccharide compounds might inhibit tumor growth. This effect of mushrooms is postulated to be due to their ability to modulate immune system function rather than a direct effect on cancer cells (1–3).

The majority of studies on mushrooms have been conducted outside of the United Sates and almost all the studies have used exotic mushrooms. In contrast, white button mushrooms (Agaricus bisporus) (WBM),3 a strain of mushroom that represents 90% of total mushrooms consumed in the United States, is much less studied for its health benefit in general and little is known about its immunologic effect in particular. Our recent study (4) showed that dietary supplementation with WBM enhanced natural killer (NK) cell activity through increasing interferon (IFN){gamma} and tumor necrosis factor (TNF){alpha} production in mice. We also observed a trend for increased lymphocyte proliferation and interleukin (IL)-2 production in mice fed mushrooms compared with those fed the control diet. These results suggest that WBM may promote innate and cell-mediated immune function.

Innate and adaptive immunity are 2 different, but interrelated, functions of the immune system. Innate immune response is quick and fully functional in fighting against invading microorganisms without requiring previous encounters with the pathogens. In some cases, this arm of immunity alone is sufficient to prevent entry of invading microorganisms and destroy them. In other cases, however, innate immunity fails to prevent entry of invading microorganisms into the body and by itself cannot clear them. The body then depends on adaptive immunity, i.e. cell-mediated and humoral immunity, to mount a more efficient and sustained response in fighting these invading microorganisms as well as developing a memory to prevent future infection by the same microorganisms. Innate and adaptive immune systems are closely linked. An important link between these 2 arms of the immune system is the antigen presenting cells (APC) that are capable of recognizing, taking up, processing, and eventually presenting a variety of foreign antigens to T cells to initiate the adaptive immune response. There are 3 professional APC, i.e. dendritic cells (DC), macrophages, and B cells. Among them, DC are widely accepted as the most efficient APC capable of inducing a protective adaptive response as well as maintaining tolerance to self-antigens (5,6). In addition, DC are directly involved in regulation of other innate immune functions such as promoting activation of NK cells and their effector function (7–9).

As mentioned above, we previously found that WBM enhanced NK cell activity, increased IFN{gamma} and TNF{alpha} production, and tended to increase lymphocyte proliferation and IL-2 production (4). Recent studies have demonstrated that polysaccharides isolated from some regional edible fungi/mushrooms enhance DC maturation and function (10–15). These results may represent a potential application of these dietary components for enhancement of certain types of specific immunity such as those related to efficacy of vaccination for microbial infection and cancer immunotherapy given that DC play an important role in these processes. However, the effect of whole WBM, the most common strain of mushroom, on DC functions has not been determined and is the subject of the present investigation. Our results showed that WBM supplementation promoted maturation of DC as well as their ability to present antigen to T cells.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
    Mice. Pathogen-free C57BL/6J mice were purchased from Harlan Sprague Dawley and DO11.10 and BALB/c mice were purchased from Jackson Laboratory. All mice were male and 3–4 mo old when used in the experiments. C57BL/6J mice were used to determine the effect of WBM on DC maturation and DO11.10 and BALB/c mice were used to determine the effect of WBM on APC function of DC as specified below. Mice were individually housed in cages maintained at a constant temperature and humidity with a 12-h-light:-dark cycle. Mice consumed water and an autoclaved commercial nonpurified diet (Teklad 7012, Harlan Teklad) ad libitum. At the end of the study, mice were killed by CO2 asphyxiation and exsanguination. All conditions and handling of the animals were approved by the Animal Care and Use Committee of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University and conducted according to the NIH Guidelines for the Care and Use of Laboratory Animals.

    Mushroom concentrate. Fresh WBM were provided by Franklin Farms. Mushroom stems were first cut off at the level of the fruit body (crown) and each mushroom was cut into quarters. The cut pieces of mushroom were freeze-dried for 5 d and then ground to powder in a grinder. Dry matter was 7.5% of fresh weight. Mushroom solution was freshly prepared in each experiment by dissolving mushroom powder in the culture medium and passing through a 0.22-µm syringe-top filter to be sterilized.

    Bone marrow-derived DC. Bone marrow-derived DC (BMDC) were generated following a previously described method (16). Briefly, the BM cells in femurs and tibias of C57BL/6 and BALB/c mice were aseptically flushed out with complete RPMI medium using a 10-mL syringe. The complete RPMI medium was prepared by adding 25 mmol HEPES/L (Invitrogen Gibco), 2 mmol glutamine/L (Gibco), 100 kU penicillin/L, 100 mg streptomycin/L (Gibco), and 10% fetal bovine serum (FBS) (Gibco) to RPMI 1640 medium (Biowhittaker). BM cells were seeded into 6-well plates (Becton Dickinson Labware) at a density of 1 x 109 cells/L in maturation medium, a complete RPMI medium containing 20 µg/L granulocyte-macrophage colony-stimulating factor and 20 µg/L IL-4 (both from R&D Systems). All the cell culture experiments were conducted under 37°C, 5% CO2, and 95% humidity unless indicated otherwise. On d 2, 75% of medium was replaced with fresh maturation medium supplemented with WBM concentrate at 50, 100, or 200 mg/L. On d 5, non- and loosely adherent cells were harvested and subcultured in 24-well plates (BD Labware) containing fresh maturation medium supplemented with WBM concentrate as mentioned above. On d 6, lipopolysaccharide (LPS) (100 µg/L) was added to a separate set of cells in parallel as positive control. On d 7, all BMDC were harvested for analysis of surface marker expression, intracellular IL-12 levels, and endocytosis as described below.

    DC maturation marker expression. BMDC were incubated with phycoerythrin (PE)-conjugated anti-CD11c, and fluorescein isothiocyanate (FITC)-conjugated anti-CD40, anti-I-Ab [major histocompatibility complex (MHC) class II], anti-CD80, and anti-CD86 for 20 min at room temperature. Appropriate isotype control was used for each antibody. All anti-mouse antibodies were from BD Biosciences. Stained cells were analyzed by a FACSCalibur flow cytometer (BD Biosciences) and results were analyzed using the software Summit 4.0 (DakoCytomation).

    Intracellular IL-12 levels in BMDC. Four hours prior to BMDC harvest, brefeldin A (Sigma, 10 mg/L) was added to block IL-12 transport out of cells. DC were first stained with DC surface marker, PE-conjugated anti-mouse CD11c. After washing, cells were fixed with IC-fixation buffer (eBioscience) containing 4% paraformaldehyde and then incubated with allophycocyanin-conjugated anti-mouse IL-12 p40/p70 (BD Biosciences) in permeabilization buffer (eBioscience) for 30 min at room temperature. IL-12 levels in CD11c+ cells (DC) were analyzed by a FACSCalibur.

    Endocytosis assay. The endocytic capacity of BMDC was determined by an energy-dependent uptake of FITC-labeled dextran (42,000 Da; Sigma). BMDC were incubated in the presence of FITC-dextran (1 g/L) at 37C° for 1 h. Cells were then washed twice with cold FACS buffer (PBS containing 2% FBS) and stained with anti-CD11c (PE) Ab. FITC-dextran uptake by DC was determined using a FACSCalibur. The parallel experiments were conduced at 4 C° to determine the nonspecific adherence as background.

    Antigen presentation. Antigen-presenting function of BMDC was assessed by allogeneic T cell activation responding to a specific antigen presented by WBM concentrate-treated BMDC. BM cells isolated from BALB/c mice were differentiated and treated with WBM concentrate as described above for C57BL/6 mice. At the end of the maturation process, cells were purified by positive selection using MACS mouse DC cell isolation kit (Miltenyi Biotec). Spleens from DO11.10 mice were aseptically removed and placed in complete RPMI medium without FBS. Splenocytes were isolated as previously described (4). Purified CD4+ T cells were prepared by negative selection using MACS mouse CD4+ T cell isolation kit (Miltenyi). T cell division was determined using a fluorescent dye tracking method as described before (17). Briefly, CD4+ T cells labeled fluorescein diacetate succinimidyl ester (CFSE; Molecular Probes) at 1 x 106 per well in a 24-well plate were cocultured with 2 x 105 per well BMDC in the presence of ovalbumin (OVA; 100 mg/L, Sigma) for 48 h. Supernatants were collected for IL-2 analysis by ELISA (BD Pharmingen) and fresh complete RPMI medium was added to continue the incubation for 24 h. Cells were harvested and green fluorescence from CFSE was collected and analyzed with a FACSCalibur. To determine T cell proliferation, CD4+ T cells (1.5 x 105 per well) and BMDC (3 x 104 per well) were cocultured in the presence of OVA (100 mg/L) as described above but in 96-well flat-bottom plates for 72 h. T cell proliferation was determined using [3H]-thymidine incorporation as previously described (4).

    Statistical analysis. Results are expressed as means ± SEM. Statistical analysis was conducted using SYSTAT 10 statistical software. Significant differences were determined using ANOVA for overall treatment effect and was followed by Fisher's least significance difference post hoc test for individual comparisons. Significance was set at P < 0.05.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
    WBM increases expression of DC maturation markers. Addition of WBM to the culture medium during DC maturation increased the expression of, in both percentage of positive cells and per cell density, costimulatory markers (CD40, CD80, and CD86) and MHC class II in a dose-dependent manner (Fig. 1; Table 1). As expected, LPS, a potent inducer of DC maturation and activation (18,19) serving as a positive control, strongly induced expression of the maturation markers on DC, which was well reflected in the corresponding functional changes in DC themselves as well as in T cell responses to a specific antigen presented by the matured DC (see below).


Figure 1
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  		FIGURE 1  WBM increases expression of BMDC maturation markers in BMDC from C57BL/6 mice. A fraction of DC stimulated by LPS (100 µg/L) for 24 h was used as the positive control. M0–200: mushroom concentrations in mg/L. Results are representative of 4–6 independent experiments. See Table 1 for summary of these data.

 

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  		TABLE 1 Effect of WBM on expression of DC maturation markers in C57BL/6 mice1

 
    WBM-enhanced DC maturation is manifested by the corresponding alteration in DC function. With the process of maturation, the ability of DC to produce IL-12 increases while their endocytic function decreases. Accordingly, we found that the mushroom treatment increased IL-12 production (Fig. 2) and decreased endocytosis of dextran particles (Fig. 3) by BMDC.


Figure 2
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  		FIGURE 2  WBM increases IL-12 production by BMDC from C57BL/6 mice. Cells were surface stained with CD11c (DC marker) followed by intracellular staining with IL-12 p40/p70. LPS: 100 µg/L. Results are means ± SEM, n = 5. Means without a common letter differ, P < 0.05.

 

Figure 3
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  		FIGURE 3  WBM decreases endocytic capacity of BMDC from C57BL/6 mice. BMDC were incubated in the presence of FITC-dextran (1 g/L) at 37C° for 1 h and FITC-dextran uptake in DC (CD11c+ cells) was determined using a FACSCalibur. Parallel experiments were conduced at 4 C° to determine the nonspecific adherence as background. LPS: 100 µg/L. The histograms show a representative experiment and bar figures are means ± SEM of 6 independent experiments. Means without a common letter differ, P < 0.05.

 
    WBM increases antigen-presenting function of DC as demonstrated by increased T cell proliferation and IL-2 production. An important function of DC is to present specific antigens to T cells and initiate adaptive immune response. We found that CD4+ T cells incubated with the WBM-treated DC had higher proliferative response to specific antigen OVA compared with the T cells incubated with control DC (without addition of WBM) (Fig. 4). The cultures of T cells and DC without OVA had a low proliferation level, indicating that the reaction was antigen specific. Using the CFSE tracking method to determine clonal expansion of exclusive CD4+ population, we further confirmed the effect of WBM on antigen presentation by BMDC (Fig. 5).


Figure 4
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  		FIGURE 4  WBM-treated BMDC increases CD4+ T cell proliferation in response to specific antigen OVA. BM cells isolated from BALB/c mice were differentiated and treated with WBM and DC were purified. Purified CD4+ T cells were prepared from the spleens of DO11.10 mice. CD4+ T cells (1.5 x 105 per well) and BMDC (3 x 104 per well) were cocultured in the presence of OVA (100 mg/L) for 72 h. The cultures of T cells and DC without OVA were used as unstimulated control. Cell proliferation was quantified by [3H]-thymidine incorporation. Results are means ± SEM, n = 6. Means without a common letter differ, P < 0.05.

 

Figure 5
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  		FIGURE 5  WBM-treated BMDC increases CFSE-tracked CD4+ T cell division in response to specific antigen OVA. MBDC from BALB/c mice and CD4+ T cells from DO11.10 mice were prepared and treated as described in Figure 4 except that CD4+ T cells were labeled with CFSE. Cells were harvested, stained with PE-conjugated anti-CD4, and analyzed with a FACSCaliber. CFSE was collected in CD4+ population. LPS: 100 µg/L. Results are representatives of 5 independent experiments.

 
IL-2 is T cell growth factor and its production by T cells is commonly used as an indicator of T cell activation. Consistent with the findings in T cell proliferation, CD4+ T cells incubated with the WBM-treated DC produced more IL-2 in response to specific antigen OVA compared with those incubated with control DC (Fig. 6).


Figure 6
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  		FIGURE 6  WBM-treated BMDC increases IL-2 production by CD4+ T cells in response to specific antigen OVA. MBDC from BALB/c mice and CD4+ T cells from DO11.10 mice were prepared and treated as described in Figure 4. CD4+ T cells at 1 x 106 per well were cocultured with 2 x 105 per well BMDC in the presence of OVA (100 mg/L) for 48 h. Supernatants were collected for IL-2 analysis by ELISA. Results are means ± SEM, n = 5. Means without a common letter differ, P < 0.05.

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
In this study, we have shown that supplementation with WBM during DC differentiation and maturation enhances DC maturation as demonstrated by increased expression of maturation markers, IL-12 production, and decreased endocytic capacity. Upregulated expression of maturation markers on DC is associated with changes in both innate and adaptive immunity. In addition, IL-12 is a critical cytokine that bridges innate and adaptive immune systems (20,21). One major role of IL-12 is its induction of other cytokines, particularly IFN{gamma}. IL-12 induces IFN{gamma} production in NK and T cells and enhances cytolytic activity of these cells (20,21). IL-12 also drives development of CD4+ T cells into Th1 cells and promotes cell-mediated immune response (20,21). In this regard, it is interesting to note that previously we found WBM increased NK activity and IFN{gamma} production in spleen cells (4). Taken together, these results suggest that improved DC maturation following WBM supplementation may contribute to the previously observed effect of WBM on NK cells and IFN{gamma} production.

As the most important professional APC, a crucial role of DC is to present processed antigens to T cells so that T cells can develop a specific immune response to particular antigens. Antigen-presenting function of matured DC is often used as a key index to further confirm the extent of DC maturation. In this study, we used the T cells from transgenic DO11.10 mice as responder T cells. These T cells predominantly express a T cell receptor that recognizes OVA 323–339 peptide. After WBM-treated DC were incubated with the T cells from DO11.10 mice in the presence of OVA, we found a significantly higher clonal expansion of allogeneic T cells as indicated by enhanced cell proliferation and cell cycle division. Consistent with this, IL-2 production by these T cells also increased. These data suggest that WBM can potentially affect antigen-specific T cell activation through modulating DC maturation. Because DC have been shown to directly promote antibody production and proliferation of B cells stimulated by CD40L on activated T cells (22,23), these data may also suggest a possibility that the WBM-induced increase in DC maturation might have an effect on B cells. This, however, needs to be confirmed in future studies by directly assessing the effect of WBM on B cell function.

In this study, we used whole mushroom concentrate; thus, it is not clear what specific components of WBM contributed to the observed effect on DC. Previous studies using polysaccharides isolated from a variety of regional edible fungal species (10–15) reported similar effects on DC to those reported here, suggesting that the DC-activating effect of WBM may be attributed to its polysaccharide content. β-Glucans, particularly β-1, 3-glucans with β-1, 6 linked side chains, are predominant polysaccharides present in the majority of mushrooms. The innate immune system has evolved to gain an ability to recognize pathogens by germline-encoded receptors that are referred to as pattern-recognition receptors, such as toll-like receptors. Because β-glucans are major cell wall structural components in fungi and some plants and bacteria, but are not found in animals, these carbohydrates are considered to be pathogen-associated molecular patterns (24). It has been suggested that β-glucans can stimulate DC by acting on receptors dectin-1, complement receptor type 3 (CR3 = D11b/CD18), and toll-like receptor-2 and -4 (24–26). Activation of DC by these molecules can induce both innate and adaptive mechanisms to promote effective immune responses against tumor development and microbial infection.

In this study, we employed an in vitro supplementation model to determine the effect of WBM on DC maturation and antigen-presenting function. While we are aware that an in vivo (feeding) design would have been more relevant in defining the effect and efficacy of consuming mushrooms as a nutritional intervention, there were some limitations for taking this approach in the current study. It is well known that difficulty in obtaining an adequate number of DC has impeded research in the field (27). Therefore, researchers have used DC obtained through differentiation from progenitors ex vivo. In the majority of studies, researchers have used mouse DC derived from bone marrow cells and human DC from blood monocytes after in vitro induction with granulocyte-macrophage colony-stimulating factor and IL-4 (28–31). In a typical protocol, induction of progenitor cells into mature DC takes 7 to 10 d after cells are isolated from the host. Thus, it is unlikely that the effect of any supplement provided to the host through feeding would be retained at substantial levels after such an extended in vitro procedure. Whether the doses used in the current study have any relevance to dietary consumption in form of whole food or extract supplements is not clear and no relevant information is available to make a speculation. Future in vivo studies may provide some clues. Nevertheless, the results from this study are useful in guiding further investigation in defining the immunologic effect of WBM. Specifically, having observed the effectiveness of WBM on maturation of DC following in vitro supplementation, we now plan to embark on the more logistically difficult studies in which the effect of WBM on in vivo maturation of DC can be determined. Future studies should also further determine how subtypes of DC are affected by mushrooms as different mature DC have been shown to induce either immunogenic (T helper) or immunotolerogenic regulatory T cells (T reg) (32). Another limitation of the study is that the effective components of mushrooms in the in vitro system such as β-glucans might not be available to the peripheral immune cells following in vivo feeding, given their indigestibility, which would limit their passage through the absorptive system. However, we and others have reported that feeding mushrooms to animals does affect the function of the peripheral immune system (4,33–35). It is likely that DC present in mucosal lymphoid tissues have access to the gut content (36,37) and as such, are allowed to be exposed to a high concentration of the polysaccharides after mushroom consumption. Therefore, it is likely that oral administration of mushrooms would be effective in modulating DC functions similar to what we have observed following in vitro supplementation.

In summary, the results from this study show that WBM promote DC maturation and these mushroom-treated DC are more effective in activating specific T cell responses through an improvement in their antigen-presenting function. This effect of mushrooms could have significant implications in inducing both innate and adaptive immunity against tumor development and microbial infection. Further studies are needed to determine the effect of in vivo supplementation with WBM on T cell priming function of DC by employing an antigen-sensitized animal model.


   ACKNOWLEDGMENTS
 
The authors thank Stephanie Marco for help in preparation of the manuscript.


   FOOTNOTES
 
1 Supported by a grant from the Mushroom Council and the USDA Agriculture Research Service under contract number 58-1950-7-707. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the USDA. Back

2 Author disclosures: Z. Ren, Z. Guo, S. N. Meydani, and D. Wu, no conflicts of interest. Back

3 Abbreviations used: APC, antigen presenting cell; BMDC, bone marrow-derived dendritic cell; CFSE, fluorescein diacetate succinimidyl ester; DC, dendritic cell; FBS, fetal bovine serum; FITC, fluorescein isothiocyanate; IFN, interferon; IL, interleukin; LPS, lipopolysaccharide; MFI, mean fluorescence intensity; MHC, major histocompatibility complex; NK, natural killer cell; OVA, ovalbumin; PE, phycoerythrin; TNF, tumor necrosis factor; WBM, white button mushroom. Back

Manuscript received 29 November 2007. Initial review completed 19 December 2007. Revision accepted 1 January 2008.


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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
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