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The Journal of Immunology, 2007, 179, 744 -747
Copyright © 2007 by The American Association of Immunologists, Inc.
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Cutting Edge: High Molecular Weight Hyaluronan Promotes the Suppressive Effects of CD4+CD25+ Regulatory T Cells1

Paul L. Bollyky2, James D. Lord, Susan A. Masewicz, Stephen P. Evanko, Jane H. Buckner, Thomas N. Wight and Gerald T. Nepom

Benaroya Research Institute, Seattle, WA 98101


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Hyaluronan is a glycosaminoglycan present in the extracellular matrix. When hyaluronan is degraded during infection and injury, low m.w. forms are generated whose interactions influence inflammation and angiogenesis. Intact high m.w. hyaluronan, conversely, conveys anti-inflammatory signals. We demonstrate that high m.w. hyaluronan enhances human CD4+CD25+ regulatory T cell functional suppression of responder cell proliferation, whereas low m.w. hyaluronan does not. High m.w. hyaluronan also up-regulates the transcription factor FOXP3 on CD4+CD25+ regulatory T cells. These effects are only seen with activated CD4+CD25+ regulatory T cells and are associated with the expression of CD44 isomers that more highly bind high m.w. hyaluronan. At higher concentrations, high m.w. hyaluronan also has direct suppressive effects on T cells. We propose that the state of HA in the matrix environment provides contextual cues to CD4+CD25+ regulatory T cells and T cells, thereby providing a link between the innate inflammatory network and the regulation of adaptive immune responses.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Hyaluronan (HA)3 is a widely distributed tissue extracellular matrix component characterized by a repeating disaccharide of N-acetylglucosamine and D-glucuronic acid. It is long and ranges in molecular mass from 104 to 107 Da (1), is highly charged, and can bind large amounts of water. Breakdown products are bioactive, and the quantities and ratios of differently sized HA molecules form a potential conduit for intercellular communication in tissue inflammation and repair (2).

The bioactive properties of HA vary with its size. High m.w. HA (HMW-HA) (> 2,000 saccharides and >400 kDa) serves a variety of structural and regulatory functions including lubrication of joints (3), provision of scaffolding for tissue repair in injury (4), and regulation of osmosis in inflammation (5). HMW-HA is antiangiogenic (6) and anti-inflammatory (7, 8, 9) and inhibits phagocytosis by monocytes (10). HMW-HA currently has a number of clinical applications, including treatment for osteoarthritis of the knee and the prevention of postsurgical abdominal adhesions (11). In contrast, low m.w. HA fragments (LMW-HA) (<16 saccharides and <3 kDa) generated during infection and injury through the action of hyaluronidases can promote angiogenesis and proinflammatory responses (12, 13, 14, 15). The abundance of HA within the tissue matrix and the dynamic interplay between differently sized HA molecules offers a potential signaling system reflecting the state of tissue matrix integrity during injury, inflammation, or repair.

A number of receptors bind HA. The best characterized of these is CD44, a nearly ubiquitous cell surface receptor that exists in multiple isoforms with distinct functional characteristics depending on alternative splicing and the expression of different exons (16). The CD44 expressed on resting T cells and monocytes is functionally inactive and binds HA only after TCR triggering or after activation by proinflammatory cytokines including TNF-{alpha} and IFN-{gamma} (17). Activation with mitogenic stimuli causes the expression of CD44 isomers CD44-v9 and CD44-v6, which are absent on resting T cells (18). In mice, TCR stimulation up-regulates an activated form of CD44 in the most actively suppressive subset of CD4+CD25+CD127low regulatory T cells (TR) (19).

We have asked whether the local state of HA in the extracellular matrix impacts TR function. We demonstrate that both HMW-HA and LMW-HA bind to TR and that the size of HA differentially impacts TR activation and TR-mediated suppression of CD4+CD25– proliferative responses. HMW-HA enhancement of activated regulatory T cells provides a potential sensor mechanism linking the state of tissue matrix integrity and the adaptive immune response.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Disclosures
 References
 
Reagents

HA with a molecular mass of 1.5 x 106 kDa was obtained (Genzyme). Fluorescein-labeled HA was prepared by a standard method (20). LMW-HA was prepared by digestion of HMW-HA with Streptomyces hyaluronidase, followed by filtration through Centricon microconcentrators (Amicon) to produce fragments of <3 kDa as described previously (21). HA of 30 kDa was generated for use as a size reference only (Fig. 1). Pep-1, a peptide inhibitor of HA binding (22), was obtained from Sigma-Genosys. A CD44 blocking mAb, clone Bu75, was obtained from Ancell.


Figure 1
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  		FIGURE 1. Binding of FITC-labeled HA. A, One percent agarose gel separation of 1.5 x 106 kDa HA (HMW-HA) and 3 kDa HA (LMW-HA). HA of 30 kDa is shown as a size marker but was not used for any of the experiments in this work. B, HA binding to CD4+CD25– T cells (TC). C, Binding to CD4+CD25+ TR. In B and C the binding of a control FITC-labeled IgG1 is shown (gray-filled histogram) as is FITC-HMW-HA (black lines) and FITC-LMW-HA (gray lines). D, Blocking of FITC-HMW-HA binding to TR. Unblocked FITC-HMW-HA binding is shown (thick black line) as is binding following the pretreatment of FITC-HA with a specific peptide inhibitor of HA binding, PEP-1 (thin black line), pretreatment with on-labeled HMW-HA (gray-filled histogram), and pretreatment with a CD44 blocking mAb (dotted line).

 
Clinical samples

Peripheral blood samples were obtained with informed consent from healthy volunteers participating in a research protocol approved by the institutional review board of the Benaroya Research Institute at Virginia Mason Medical Center (Seattle, WA).

Isolation of regulatory T cells

PBMC were prepared by centrifugation over Ficoll-Hypaque gradients. The CD4+ T cell population was first purified using the Dynal CD4 positive isolation kit (Invitrogen Life Technologies). Cells were then stained with anti-CD25 Abs (BD Pharmingen) and in most cases for CD127 (BD Pharmingen). Cell fractions were subsequently isolated using a FACSVantage flow cytometer cell sorter, resulting in the recovery of CD4+CD25+CD127low populations; purity was reliably >98%.

Cell marker staining and flow cytometry analysis

For detection of HA binding, cells were washed and then incubated in vitro with FITC-labeled HA for 60 min. To stain for FoxP3, cells were fixed, permeabilized, and stained using an FoxP3 Ab kit (eBiosciences). Flow cytometric analyses were performed on a FACScalibur flow cytometer with CellQuest (BD Biosciences) and WinMDI (J. Trotter, University of California San Diego, La Jolla, CA) software.

Activation of regulatory T cells

CD25+ cells were activated with 5 µg/ml plate-bound anti-CD3 (OKT3) and 2.5 µg/ml soluble anti-CD28. Cells were removed from the plate-bound Ab after 24 h. Alternatively, activation was with Xcyte Dynabeads (Invitrogen Life Technologies) at a ratio of 1 bead per 10 cells. Xcyte beads are super paramagnetic beads to which anti-CD3 and anti-CD28 have been covalently linked. Media was supplemented with 200 IU/ml IL-2 (Chiron).

Characterization of CD44 isomer populations

CD4+ cells were isolated from PBMC via Dynal positive isolation and treated with the murine unlabeled antihuman Abs 11.9 (CD44-v6), 11.24 (CD44-v9), 11.10 (CD44-v4) (18), and G44-26 (promiscuous for CD44 isomers) (BD Pharmingen). Cells were stained with the goat anti-mouse IgG (whole molecule), R-PE-labeled secondary Ab P9670 (Sigma-Aldrich), sorted for CD25 expression by flow cytometry, and subsequently analyzed for FOXP3 expression using anti-FOXP3 mAb (BioLegend). For the characterization of CD44 isomer populations on activated cells, TR were isolated from the same donor using CD4+ Dynal selection and flow cytometry as described above and activated with Xcyte beads supplemented with 200 IU/ml IL-2. After 3 days there was no discernible CD25 Ab bound to the cells seen upon FACS analysis (data not shown). Staining was performed for CD44 isomers. Half of each population then underwent FoxP3 staining and the other half was treated with 20 µg/ml FITC-labeled HMW-HA.

Suppression of proliferation by CD25+ cells

For the suppression assay, CD4+CD25– cells (2,500 cells per well), CD4+CD25+ cells (2,500 cells per well), or both (2,500 cells per well each) were activated with either 5 µg/ml soluble anti-CD3 and 2.5 µg/ml soluble anti-CD28 along with T cell-depleted accessory cells (25,000 cells per well) or 300 Xcyte beads per well and no APC. HA was added to the wells at the initiation of the experiment. Alternatively, the TR were incubated in HA overnight and washed three times before their addition to the assay (pulsed) as noted. No IL-2 was added to these assays. Proliferation was measured by adding 1 µCi of [3H]thymidine during the final day of a 5- to 6-day assay.

Expanded regulatory T cells

In vitro expanded TR were generated using a previously described method (23). In brief, flow-purified CD4+CD25+ T cells were stimulated with anti-CD3 and anti-CD28 coupled to Xcyte beads supplemented with 2,000 IU/ml IL-2 in complete medium. Cultures were monitored daily and maintained with IL-2 supplemented complete medium. Expanded cells were washed before their incorporation in suppression assays.

Statistical analysis

Data are expressed as mean values ± SE except where otherwise noted. A Student’s paired t test was used to determine significance.


   Results and Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
HMW-HA binding is enhanced on activated human TR

FITC-labeled HMW-HA or an equivalent amount of FITC-labeled LMW-HA (Fig. 1A) were added to resting (unactivated) flow cytometry-sorted TR and CD4+CD25– T cells as well as TR from the same donor 96 h following activation with anti-CD3 and anti-CD28. Binding to unactivated cells was minimal, while binding of both forms of HA was enhanced following activation (Fig. 1, B and C). This is consistent with studies which have reported FITC-HA binding to activated but not unactivated T cells (24). The specificity of HA binding to TR was demonstrated through inhibition in the setting of PEP-1, a peptide inhibitor of HA binding (22), through competitive exclusion in the setting of coadministration of non-FITC labeled HA, and by binding blockade using an anti-CD44 blocking mAb (Fig. 1D).

We sought to characterize differences in CD44 that occur following TCR stimulation which might account for the differential binding of HA to activated TR. We found that CD44-v6 and CD44-v9 were substantially up-regulated upon TR activation, whereas CD44-v4 was not (Fig. 2, A and B). Fluorescein-labeled HMW-HA bound most strongly to cells most highly expressing CD44-v6 (Fig. 2C) and CD44-v9 (data not shown). Higher expression of CD44-v6 correlated with the expression of the TR-associated signaling molecule FoxP3 (Fig. 2B) as did the expression of total CD44 (Fig. 2D). These results are in keeping with the CD44 isomer expression patterns reported for activated and unactivated T cells (18) and with murine data suggesting that TR expressing an activated form of CD44 were the most potent suppressors of proliferative effects (19). CD44-v6 stimulation has been shown to provide a strong proliferative signal via MAPKs and is also associated with CD25 up-regulation (25).


Figure 2
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  		FIGURE 2. CD44 isomers on TR. A and B, Binding of Abs against CD44v6, CD44v9, and CD44v4 preactivation (A) and 72 h postactivation (B). C, The relative binding of FITC-labeled HMW-HA at 20 µg/ml to TR with high (i) and low (ii) expression of CD44v6 as shown by fluorescence gates (i) and (ii) in B (left panel). D, The binding of a general CD44 Ab, nonrestricted to any particular CD44 isomer, in relation to FoxP3 expression on activated TR.

 
HMW-HA up-regulates FoxP3 and augments the suppressive capacity of human TR

FoxP3 expression falls on TR without continuous resupplementation with IL-2 (Fig. 3A). However, treatment with HMW-HA at 20 µg/ml led to the maintenance of high expression of FoxP3 (Fig. 3B). LMW-HA treatment had a more modest effect at this same concentration.


Figure 3
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  		FIGURE 3. FoxP3 expression is modulated by HA administration. A, TR on days 2 and 7 postisolation and activation showing intracellular staining with anti-FOXP3 mAb. T cell (TC) expression of FoxP3 at 2 days postisolation also but without activation is shown for reference. B, FoxP3 expression on TR 7 days postactivation following a 24-h treatment with 20 µg/ml HMW-HA or LMW-HA. Results are representative of three experiments.

 
HMW-HA, but not LMW-HA, enhances the antiproliferative activity of TR (Fig. 4A). The HA concentration used (20 µg/ml) is within the physiologic range (26). For this experiment, expanded TR were pulsed in HA overnight and washed three times to remove free HA before their addition to CD4+CD25– responder T cells and APC in a TR assay. Responder cell proliferation was significantly more inhibited by TR that had been exposed to HMW-HA than by TR that had not. In a separate experiment, HMW-HA or LMW-HA (Fig. 4, B vs C) was added directly to a suppression assay using fresh TR and Xcyte Dynabeads as APC to exclude the contribution of HA-APC interactions. Over a wide variety of effector/responder cell ratios, suppression of autologous CD4+CD25– T cell proliferation was enhanced by 20 and 100 µg/ml HMW-HA, but not by LMW-HA at either concentration. In this experiment, the ability of HMW-HA to enhance TR suppression activity appears to be due to its interaction with TR and not due to an effect on APC or on the responder cells. However, HMW-HA also has direct effects on responder cell proliferation, albeit only at high concentrations (Fig. 5). Because LMW-HA, generated from identical HMW-HA, had no such effects, it is unlikely that this antiproliferative effect of HMW-HA is due to contaminants present in clinical grade HA.


Figure 4
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  		FIGURE 4. HA effects on CD4+CD25+ TR suppressor function. A, Expanded TR were incubated with HA overnight and then washed 3x before their addition to a standard suppression assay with CD4+CD25– responder cells and irradiated allogeneic non-CD4 cells as APC. *, p < 0.014 for the comparison of responder cell proliferation in the assay with TR treated with HMW-HA at 20 µg/ml vs no HA; **, p < 0.008 for the comparison of LMW-HA at 20 µg/ml vs no HA. B and C, Suppression assays using fresh TR with autologous responder cells and Xcyte beads as artificial APC. HMW-HA and LMW-HA were both added directly to the assay at 20 µg/ml. B, Dose titration for HMW-HA. §, p < 0.05 for the comparison of HMW-HA at 100 µg/ml vs no HA; #, p < 0.05 for the comparison of HMW-HA at 20 µg/ml vs no HA. C, Dose titration for LMW-HA. The initial number of responder cells is constant throughout.

 

Figure 5
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  		FIGURE 5. Direct effects of hyaluronan on proliferation on CD4+CD25– T cells. A, Data are shown for four combined experiments where HMW-HA was added directly at 20 µg/ml to CD4+CD25– T cells. To allow for cross-experiment comparisons, the amount of proliferation in the HA-untreated arm of each experiment was defined as "1." No significant direct effects of HA on CD4+ T cell responder proliferation were seen at 20 µg/ml HMW-HA. B, Data are also shown for a titration of HMW-HA concentrations. Only HMW-HA at a concentration of 100 µg/ml significantly suppressed proliferation. Significance was determined using a Student’s t test.

 
In summary

We describe a system of differential effects on human TR by full-length HA and its degradation product. HMW-HA binding to activated TR is associated with increased expression of FoxP3, augmentation of regulatory T cell function, and direct effects on T cell proliferation.

We propose that the state of HA in the local environment is one mechanism by which regulatory cells receive cues about the inflammatory milieu. This is consistent with previous reports of HMW-HA exerting an anti-inflammatory effect on a variety of cell types (6, 7, 8, 9, 10, 11) and extends this model to the regulation of adaptive responses. Innate recognition pathways are known to be crucial for the signaling of "danger" displayed through soluble bioactive mediators and sensed through TLR and other pattern recognition receptors; in this context we propose that HMW-HA contributes to the maintenance of immune homeostasis in uninjured tissue and effectively communicates an "all-clear" signal after tissue matrix integrity has been restored. HMW-HA may provide a mechanism for dampening the cellular immune response following the successful resolution of tissue damage or disease.


   Acknowledgments
 
We thank Nathan Standifer for review of the manuscript and Carrie Rosenberger for helpful advice.


   Disclosures
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 Abstract
 Introduction
 Materials and Methods
 Results and 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 National Institutes of Health Grants DK46635 (to J.H.B.), HL18645, and DK53004 and funds from the Juvenile Diabetes Research Foundation (The Center for Translational Research at Benaroya Research Institute, Seattle, WA). Back

2 Address correspondence and reprint requests to Dr. Paul L. Bollyky, Benaroya Research Institute, 1201 Ninth Avenue, Seattle, WA 98101. E-mail address: pbollyky{at}benaroyaresearch.org Back

3 Abbreviations used in this paper: HA; hyaluronan; HMW-HA, high m.w. HA; LMW-HA; low m.w. HA; TR, CD4+CD25+ regulatory T cell. Back

Received for publication January 4, 2007. Accepted for publication May 18, 2007.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 

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