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A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells.

ABSTRACT: Tissue-derived adenosine, acting via the adenosine A(2A) receptor (A(2A)R), is emerging as an important negative regulator of T-cell function. In this report, we demonstrate that A(2A)R stimulation not only inhibits the generation of adaptive effector T cells but also promotes the induction of adaptive regulatory T cells. In vitro, antigen recognition in the setting of A(2A)R engagement induces T-cell anergy, even in the presence of costimulation. T cells initially stimulated in the presence of an A(2A)R agonist fail to proliferate and produce interleukin-2 and interferon (IFN)-gamma when rechallenged in the absence of A(2A)R stimulation. Likewise, in an in vivo model of autoimmunity, tissue-derived adenosine promotes anergy and abrogates tissue destruction. Indeed, A(2A)R stimulation inhibits interleukin-6 expression while enhancing the production of transforming growth factor-beta. Accordingly, treating mice with A(2A)R agonists not only inhibits Th1 and Th17 effector cell generation but also promotes the generation of Foxp3(+) and LAG-3(+) regulatory T cells. In this regard, A(2A)R agonists fail to prevent autoimmunity by LAG-3(-/-) clonotypic T cells, implicating an important role for LAG-3 in adenosine-mediated peripheral tolerance. Overall, our findings demonstrate that extracellular adenosine stimulates the A(2A)R to promote long-term T-cell anergy and the generation of adaptive regulatory T cells.

SUBMITTER: Zarek PE

PROVIDER: S-EPMC2200810 | biostudies-other | 2008 Jan

REPOSITORIES: biostudies-other

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A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells.

Zarek Paul E PE Huang Ching-Tai CT Lutz Eric R ER Kowalski Jeanne J Horton Maureen R MR Linden Joel J Drake Charles G CG Powell Jonathan D JD

Blood 20071001 1

Tissue-derived adenosine, acting via the adenosine A(2A) receptor (A(2A)R), is emerging as an important negative regulator of T-cell function. In this report, we demonstrate that A(2A)R stimulation not only inhibits the generation of adaptive effector T cells but also promotes the induction of adaptive regulatory T cells. In vitro, antigen recognition in the setting of A(2A)R engagement induces T-cell anergy, even in the presence of costimulation. T cells initially stimulated in the presence of ...[more]

PMID: 17909080

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Project description:Autophagy, a homeostatic pathway upregulated during cellular stress, is decreased in osteoarthritic chondrocytes and this reduction in autophagy is thought to contribute to the development and progression of osteoarthritis (OA). The adenosine A2A receptor (A2AR) is a potent anti-inflammatory receptor and deficiency of this receptor leads to the development of OA in mice. Moreover, treatment using liposomally conjugated adenosine or a specific A2AR agonist improved joint scores significantly in both rats with post-traumatic OA (PTOA) and mice subjected to a high fat diet obesity induced OA. Importantly, A2AR ligation is beneficial for mitochondrial health and metabolism in vitro in primary and the TC28a2 human cell line. An additional set of metabolic, stress-responsive, and homeostatic mediators include the Forkhead box O transcription factors (FoxOs). Data has shown that mouse FoxO knockouts develop early OA with reduced cartilage autophagy, indicating that FoxO-induced homeostasis is important for articular cartilage. Given the apparent similarities between A2AR and FoxO signaling, we tested the hypothesis that A2AR stimulation improves cartilage function through activation of the FoxO proteins leading to increased autophagy in chondrocytes. We analyzed the signaling pathway in the human TC28a2 cell line and corroborated these findings in vivo in a metabolically relevant obesity-induced OA mouse model. We found that A2AR stimulation increases activation and nuclear localization of FoxO1 and FoxO3, promotes an increase in autophagic flux, improves metabolic function in chondrocytes, and reduces markers of apoptosis in vitro and reduced apoptosis by TUNEL assay in vivo. A2AR ligation additionally enhances in vivo activation of FoxO1 and FoxO3 with evidence of enhanced autophagic flux upon injection of the liposome-associated A2AR agonist in a mouse obesity-induced OA model. These findings offer further evidence that A2AR may be an excellent target for promoting chondrocyte and cartilage homeostasis.

Dataset Information

A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells.

Publications

A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells.

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