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The Journal of Immunology, 2006, 177: 2765-2769.
Copyright © 2006 by The American Association of Immunologists, Inc.

CUTTING EDGE

Cutting Edge: Critical Role for A2A Adenosine Receptors in the T Cell-Mediated Regulation of Colitis1

Makoto Naganuma, Elizabeth B. Wiznerowicz, Courtney M. Lappas, Joel Linden, Mark T. Worthington and Peter B. Ernst2

Department of Internal Medicine, University of Virginia, Charlottesville, VA 22908


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
A2A adenosine receptors (A2AAR) inhibit inflammation, although the mechanisms through which adenosine exerts its effects remain unclear. Although the transfer of regulatory Th cells blocks colitis induced by pathogenic CD45RBhigh Th cells, we show that CD45RBlow or CD25+ Th cells from A2AAR-deficient mice do not prevent disease. Moreover, CD45RBhigh Th cells from A2AAR-deficient mice were not suppressed by control CD45RBlow Th cells. A2AAR agonists suppressed the production of proinflammatory cytokines by CD45RBhigh and CD45RBlow T cells in association with a loss of mRNA stability. In contrast, anti-inflammatory cytokines, including IL-10 and TGF-beta, were minimally affected. Oral administration of the A2AAR agonist ATL313 attenuated disease in mice receiving CD45RBhigh Th cells. These data suggest that A2AAR play a novel role in the control of T cell-mediated colitis by suppressing the expression of proinflammatory cytokines while sparing anti-inflammatory activity mediated by IL-10 and TGF-beta.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Crohn’s disease and ulcerative colitis are chronic, relapsing inflammatory bowel diseases (IBD).3 Although the etiology of IBD remains unknown, recent studies suggest that disease results from an inappropriately regulated immune response to enteric Ags in a genetically susceptible host (1, 2, 3, 4). In animal models of colitis, there is often a marked increase in Th1 cells (5, 6) and their ability to cause disease can be attenuated by subsets of Th cells that mediate some sort of regulatory activity (7, 8). Several mechanisms regulate the host response to luminal Ags, including oral tolerance, a state of hyporesponsiveness that controls the response to dietary or microbial Ags that persist in the lumen (2). Th cells resembling regulatory T cell (Treg) also respond to persistent infection (2, 4, 7, 9).

Adenosine is a signaling molecule released from inflamed or hypoxic tissues. The multiple physiological responses controlled by adenosine are mediated by four G protein-coupled receptors (A1, A2A, A2B, and A3), depending on cell type and species (10). The A2A adenosine receptors (A2AAR) are of interest because their activation on immune cells produces a response that, in general, can be categorized as anti-inflammatory (10, 11, 12). Recent studies (10) show that adenosine analogs limit collateral damage associated with severe inflammation, including colitis (13) and ileitis (14). In this study, these data suggest that A2AAR play a critical role in the T cell-mediated regulation of colitis due to their novel effects on T cell cytokine production.


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

C57BL/6 mice and SCID mice were purchased from The Jackson Laboratory, whereas A2AAR-deficient mice (A2AAR–/– mice inbred onto the C57BL/6 background (15) were maintained in a conventional animal care facility at the University of Virginia (Charlottesville, VA). All procedures were approved by the animal care and use committee at the University of Virginia.

Purification of T cells

Splenocytes from 8- to 10-wk-old C57BL/6 or A2AAR–/– mice were enriched using CD4 microbeads (L3T4; Miltenyi Biotec) (16), while purity was confirmed by flow cytometry and ranged from 90 to 99%. The CD4+ Th cells were then sorted into subsets (>98% purity) based on the expression of CD4+, CD45RB, and CD25 (16).

Adoptive transfer studies

CD45RBhigh, CD45RBlow, or CD25+ CD4+ Th cells from control and A2aAR–/– mice were injected i.p. into SCID recipients at 5 x 105 cells (CD45RBhigh T cells) and 1 x 105 cells (CD45RBlow or CD25+ T cells). Recipient mice were weighed weekly. After 8 wk, the colons were collected, and H&E-stained sections were evaluated using a standardized histopathological scoring system (16). In some experiments, mice receiving CD45RBhigh T cells from control mice were fed chow containing 1.875 mg/kg of ATL313 (prepared by Dr. R. Figler, Adenosine Therapeutics, Charlottesville, VA).

Stimulation with A2AR agonists

CD45RBhigh, CD45RBlow, and unfractionated CD4+ T cells (1 x 106 cells/ml) were stimulated with 10 µg/ml plate-bound anti-CD3 mAb (145–2C11), and 1 µg/ml anti-CD28 mAb (37.51) (16, 17) in the presence or absence of 100 nM ATL202, ATL146e, or ATL313 (15). In some experiments, 250 nM ZM241385 (an A2AAR antagonist) or ATL801 (an A2BAR antagonist) was added to the cultures. These compounds were provided by Dr. J. Rieger (Adenosine Therapeutics).

Cytokine assays

Supernatants were collected for cytokine protein assays and cells were harvested as a source of mRNA (17). Cytokine levels were measured using a multiplex bead array (Upstate Biotechnology) and analyzed with the Bioplex workstation and associated software (Bio-Rad). TNF-{alpha}, IFN-{gamma}, and IL-2 mRNA was measured by real-time RT-PCR using primer and dual-labeled probes (Applied Biosystems) detected in a Smart Cycler (Cepheid) and normalized against 18S rRNA as described elsewhere (16, 17). To assay mRNA stability, CD4+ Th cells were stimulated for 24 h before 5 µg/ml actinomycin D (Sigma-Aldrich) and/or 100 nM ATL-202 were added into the wells. Cells were harvested at 1, 2, 3, and 4 h, and IL-2 and IFN-{gamma} mRNA levels were measured.

Statistics

Quantitative data were expressed as mean ± SEM and compared using paired Student t tests or rank-sum tests. Values of p < 0.05 were considered significant.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
Treg from A2AAR–/– mice do not prevent wasting disease induced by pathogenic Th cells

C57BL/6 SCID mice injected with CD4+CD45RBhigh Th cells from control, C57BL/6, or A2AAR–/– mice resulted in weight loss (Fig. 1a) associated with diarrhea and rectal prolapse as described previously (6, 7). Colitis was characterized by mucosal thickening, crypt elongation, epithelial hyperplasia, goblet cell depletion, and a marked infiltration by inflammatory cells (Fig. 1b). Cotransfer of CD4+CD45RBlow Th cells from control C57BL/6 mice prevented the disease induced by CD45RBhigh Th cells from the same strain, whereas A2AAR–/– CD45RBlow cells did not. The lack of protection by A2AAR–/– CD45RBlow Th cells was not due to their contamination with large numbers of pathogenic Th cells, because CD45RBlow Th cells alone caused no disease. Moreover, disease could not be induced with the adoptive transfer of increasing numbers of CD45RBlow Th cells to the immunodeficient recipients (data not shown). CD25+ Th cells from A2AAR–/– mice also failed to prevent colitis (Fig. 2a). TNF-{alpha} mRNA levels in the colonic tissue of mice receiving CD45RBhigh and CD25+ T cells from control mice was lower than the levels observed in recipients of pathogenic CD45RBhigh T cells alone or in recipients given control CD45RBhigh and CD25+ T cells from A2AAR–/– mice.


Figure 1
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  		FIGURE 1. CD45RBlow Th cells from A2AAR–/– mice failed to prevent wasting disease and colitis. A, SCID mice received a sham injection of PBS (n = 3) CD4+CD45RBhigh cells from C57BL/6 mice (n = 6), CD4+CD45RBhigh cells from A2AAR–/– mice (n = 7), CD4+CD45RBhigh cells and CD4+CD45RBlow cells from C57BL/6 mice (n = 8), CD4+CD45RBhigh cells from C57BL/6 mice, CD4+CD45RBlow cells from A2AAR–/– mice (n = 8), CD4+CD45RBhigh cells from A2AAR–/– mice, CD4+CD45RBlow cells from C57BL/6 mice (n = 4), and CD45RBhigh and CD45RBlow cells from A2AAR–/– mice (n = 4). The data are the mean value of all observations from two separate adoptive transfer studies. B, The histology of the colons from recipient mice was examined 8 wk after transfer. Photomicrographs are all at the same magnification.

 

Figure 2
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  		FIGURE 2. CD25+ Th cells from A2AAR–/– mice failed to prevent colitis. SCID mice received CD4+CD45RBhigh cells from C57BL/6 mice, CD4+CD45RBhigh cells and CD4+CD25+ cells from C57BL/6 mice, CD4+CD25+ cells from C57BL/6 mice, and CD4+CD25+ cells from A2AAR–/– mice. The histology of the colons (n = 4) from recipient mice was examined 8 wk after transfer (A). Colonic tissues from each group were harvested and pooled. RNA was extracted, and real-time PCR was performed (B). Data for panels A and B are representative examples from two separate studies.

 
A2AAR–/– mice used as the source of the donor T cells lacked any signs of disease, including colitis. Moreover, T cell expression of CD4, CD25, CD69, CD103, and glucocorticoid-induced TNFR family-related receptor and their in vitro Treg function was comparable in C57BL/6 or A2AAR–/– mice (data not shown). These observations suggest that the lack of protection in mice receiving Th cell subsets from A2AAR–/– mice was not attributable to the presence of activated, pathogenic T cells in the CD25 or CD45RBlow preparations. Rather, these data suggest that A2AAR played an important role in controlling the response of T cells to the antigenic challenges in the gut that arise in the CD45RB transfer model.

A2AAR agonists regulate cytokine production by Th cells

A2AAR could modulate Th cell phenotype at several levels, including activation, selective cell death, trafficking, and by altering effector mechanisms. Based on initial studies, A2AAR have modest effects on activation and do not lead to T cell death (data not shown). The differentiation of Th cells in A2AAR–/– mice occurs in the presence of APC that also lack A2AAR and thus, indirect effects may account for the aberrant Th cell phenotype. Although A2AAR could modulate T cell trafficking that perturbs T cell regulation in this transfer model, previous studies have shown that Treg do not have to home to the gut to attenuate pathogenic T cells (18). Because both CD45RBhigh T cells and Treg from A2AAR–/– mice were aberrant, we speculated that A2AAR could differentially control the expression of pro- and anti-inflammatory cytokines thereby affecting their behavior in the CD45RB transfer model.

As shown in Fig. 3a, the selective A2AAR agonist ATL202 impaired the production of IFN-{gamma}, TNF-{alpha}, IL-2, and IL-4 in CD45RBhigh- or CD45RBlow-activated Th cells, whereas IL-10 was partially inhibited in CD45RBlow Th cells. The receptor specificity of the inhibition was examined by comparing three different A2AAR agonists for their effects using Th cells isolated from control or A2AAR–/– mice. Although A2AAR agonists suppressed Th cells cytokines in control mice, no significant effect was observed using T cells from A2AAR–/– mice (Fig. 3b). In contrast, IL-10 levels were decreased but persisted, and the expression of TGF-beta was not inhibited in a statistically significant manner. The specificity of the response was confirmed when the reduction of proinflammatory cytokines by A2AAR agonists was attenuated by the A2AAR antagonist ZM241385 (Fig. 3c), whereas the A2BAR antagonist ATL801 had no effect.


Figure 3
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  		FIGURE 3. Suppression of cytokine production by CD4+ T cells is mediated through the A2AAR. A, Cytokines were measured in supernatants from CD45RBhigh and CD45RBlow T cells after stimulation for 72 h in the presence or absence of ATL202. Data reflect the mean ± SEM of at least three separate experiments. *, p < 0.05, compared with untreated controls. B, Cytokines were measured in the supernatants of CD4+ T cells from control, C57BL/6 mice (BL/6), or A2AAR–/– mice after stimulation for 48 h in the presence or absence of ATL202, ATL146e, or ATL313. Data are the mean ± SEM from four separate experiments. *, p < 0.05, compared with untreated controls. C, CD4+ T cells from C57BL/6 mice were stimulated in the presence or absence of 100 nM of ATL 202, ATL146, or ATL313 with/without ZM24241385 (an A2AAR antagonist) or ATL801 (an A2BAR antagonist) for 48 h. Data reflect the mean ± SEM of four separate experiments. *, p < 0.05, compared with cells treated with the A2AAR antagonist. D, CD4+CD45RBhigh T cells from C57/BL6 mice were injected into SCID mice that were fed either control (ATL(–) n = 8) or treated chow (ATL313, n = 12) on days 29–49 after reconstitution. The photomicrographs show the colons from control or treated mice. The inflammation was scored and summarized in the graph.

 
The changes in cytokine responses mediated by A2AAR agonists reflected a hierarchy with IL-2 and IFN-{gamma} being impaired the most, whereas TNF-{alpha} was affected to an intermediate degree, and the production of IL-4, IL-10 and TGF-beta changed the least. Kinetic studies showed that IL-2 IFN-{gamma} and TNF-{alpha} expression was inhibited as early as 12 h posttreatment, whereas IL-4 was detected between 36 and 72 h (data not shown). The net effect of the treatment with A2AAR agonists was to shift the balance of pro- and anti-inflammatory cytokines as reflected, for example, in a decrease in the ratio of IFN-{gamma} to IL-10 from 14.5 to 1.61; the ratio of IL-2 to IL-10 from 3.09 to 0.82, and the ratio of IFN-{gamma} to TGF-beta from 38.6 to 3.21. One might predict that the administration of an A2AAR agonist would ameliorate disease induced by the transfer of CD45RBhigh Th cells. In fact, delivering ATL313 in the chow of mice after the adoptive transfer of CD45RBhigh Th cells attenuated the colitis (Fig. 3d).

A2AAR agonists decreased the stability of proinflammatory cytokine mRNA.

To address the mechanism by which the A2AAR agonists suppressed the production of proinflammatory cytokines, the cytokine mRNA levels in T cells from control and A2AAR –/– mice were compared after activation in the presence or absence of the different A2AAR agonists. Proinflammatory cytokine mRNA levels in Th cells from control mice were significantly decreased by ATL202, ATL146e, and ATL313 (Fig. 4a), whereas IL-10 and TGF-beta were not significantly affected (data not shown). The A2AAR agonists had no effect on cytokine mRNA levels when CD4+ T cells from A2AAR–/– mice were used.


Figure 4
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  		FIGURE 4. ATL202 decreases levels of cytokine mRNA due to a loss of mRNA stability. A, CD4+ T cells from C57/BL6 and A2AAR–/– mice were stimulated for 36 h in the presence or absence of ATL202, ATL146e, and ATL313, and mRNA was measured. The data shown are cumulative observations from four separate experiments. *, p < 0.05, compared with untreated controls. B, CD4+ T cells were stimulated and treated with actinomycin D with or without ATL202. Cells were harvested at the indicated time points, and mRNA levels were determined. All samples were collected in triplicate, and the data shown are representative of observations from three separate experiments. *, p < 0.05, compared with untreated controls.

 
Other experiments showed that A2AAR agonists do not inhibit the activation of transcription factors that regulate the expression of IL-2 and IFN-{gamma} (data not shown), leading to the possibility that they decreased levels of mRNA by affecting mRNA stability. Thus, Th cells were activated to induce cytokine mRNA expression before transcription was inhibited by the addition of actinomycin D in the presence or absence of ATL202. As predicted, when actinomycin D alone was added, cytokine mRNA began to decay spontaneously. However, the levels of mRNA for IL-2 and IFN-{gamma} decreased more rapidly (p < 0.05) in the presence of both actinomycin D and ATL202 (Fig. 4b), leading to the conclusion that the inhibition of cytokine mRNA levels in Th cells is through an effect of A2AAR agonists on mRNA stability.

The current data are the first describing the ability of A2AAR agonists to destabilize mRNA. A recent study has implicated A2BAR in the stabilization of IL-10 mRNA due to protein interactions with the 3' adenosine uracil-rich element (ARE) (19). The ARE are sites at which mRNA stability can be increased or decreased. One or more ARE are found in the 3' untranslated region of IL-2, IL-4, IL-10, IFN-{gamma}, and TNF-{alpha}. Of note, TGF-beta expression was not affected by A2AAR agonists, which is consistent with the fact that ARE have not been described in the 3' region of TGF-beta mRNA. Experiments are in progress to determine whether the various AR subtypes can differentially affect the role of ARE in controlling the stability of mRNA for pro- or anti-inflammatory cytokines.

The novel results from this study suggest A2AAR play a critical role in controlling the function T cells that regulate colitis. This conclusion is based on five observations: 1) CD45RBlow or CD25+ Th cells lacking A2AAR failed to prevent disease caused by pathogenic CD45RBhigh Th cells in an adoptive transfer model; 2) Pathogenic CD45RBhigh Th from A2AAR-deficient mice could not be inhibited by Treg from control mice; 3) A2AAR agonists markedly changed the balance of proinflammatory and anti-inflammatory cytokines expressed by Th cells during their activation; 4) an A2AAR agonist attenuated disease in vivo and; and 5) A2AAR agonists preferentially destabilized the mRNA that encodes proinflammatory cytokines. Thus, A2AAR play an important and novel role in the control Th cell function and their impact on colitis in an animal model. Stimulation through the A2AAR may provide a novel strategy to manipulate the Th cell response to the therapeutic advantage of the host.


   Acknowledgments
 
We thank Sharon Hoang, Joanne Lannigan, William Ross, and Mike Solga for technical assistance as well as Drs. Sarah A. De La Rue and Kenneth Tung for critically reviewing the manuscript.


   Disclosures
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 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
References
 
Joel Linden owns shares in Adenosine Therapeutics.


   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 the Crohn’s and Colitis Foundation of America (CCFA), National Institutes of Health Grants DK50980, AI069880, and RR00175 (to P.B.E.), and the Immunology and Cell Isolation Core as well as the Morphology/Imaging Core of the University of Virginia (Charlottesville, VA) Digestive Health Research Center (DK67629). M.N. is supported by a fellowship from the CCFA. Back

2 Address correspondence and reprint requests to Dr. Peter B. Ernst, Department of Internal Medicine, University of Virginia, P.O. Box 800708, Charlottesville, VA, 22908-0708. E-mail address: Pernst{at}virginia.edu Back

3 Abbreviations used in this paper: IBD, inflammatory bowel disease; Treg, regulatory T cell; A2AAR, adenosine 2A adenosine receptor; ARE, adenine- and uracil-rich element. Back

Received for publication March 29, 2006. Accepted for publication July 6, 2006.


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

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