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. 2014 Jul 10:5:304.
doi: 10.3389/fimmu.2014.00304. eCollection 2014.

Extracellular adenosine-mediated modulation of regulatory T cells

Akio Ohta  1 , Michail Sitkovsky  1
Affiliations

Extracellular adenosine-mediated modulation of regulatory T cells

Akio Ohta et al. Front Immunol. .

Abstract

Extracellular adenosine-dependent suppression and redirection of pro-inflammatory activities are mediated by the signaling through adenosine receptors on the surface of most immune cells. The immunosuppression by endogenously-produced adenosine is pathophysiologically significant since inactivation of A2A/A2B adenosine receptor (A2AR/A2BR) and adenosine-producing ecto-enzymes CD39/CD73 results in the higher intensity of immune response and exaggeration of inflammatory damage. Regulatory T cells (Treg) can generate extracellular adenosine, which is implicated in the immunoregulatory activity of Tregs. Interestingly, adenosine has been shown to increase the numbers of Tregs and further promotes their immunoregulatory activity. A2AR-deficiency in Tregs reduces their immunosuppressive efficacy in vivo. Thus, adenosine is not only directly and instantly inhibiting to the immune response through interaction with A2AR/A2BR on the effector cells, but also adenosine signaling can recruit other immunoregulatory mechanisms, including Tregs. Such interaction between adenosine and Tregs suggests the presence of a positive feedback mechanism, which further promotes negative regulation of immune system through the establishment of immunosuppressive microenvironment.

Keywords: A2A-adenosine receptor; A2B-adenosine receptor; adenosine; immunosuppression; regulatory T cell; tumor microenvironment.

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Figures

Figure 1
Figure 1
Endogenous immunoregulatory mechanisms from tiny molecule to cells. Molecular weight of CTLA-4 represents the approximate size of a homodimer. Tregs express CTLA-4 and produce IL-10 and adenosine.
Figure 2
Figure 2
Metabolism of extracellular adenosine and its effect on cellular immunity. The activities of CD39 and CD73 produce extracellular adenosine. Extracellular adenosine decreases by adenosine deaminase (ADA)-dependent catabolism and by cellular uptake through nucleoside transporters (NT). Adenosine in the intracellular compartment is converted to AMP by adenosine kinase (AK) or catabolized by ADA. When extracellular levels of adenosine increase, it stimulates A2AR (high-affinity) and A2BR (low-affinity) on immune cells. Adenosine is suppressive to effector T (Teff), NK, and NKT cells. The immunosuppressive activity may be further enhanced by adenosine-mediated induction of Tregs, tolerogenic antigen-presenting cells (APC), and myeloid-derived suppressor cells (MDSC).
Figure 3
Figure 3
Mechanisms of T cell regulation by extracellular adenosine. Extracellular adenosine can be produced by activities of CD39 and CD73 on cell surface. And its interaction with A2AR directly inhibits T cell activation. Tregs express both CD39 and CD73 at high levels and use adenosine for their immunoregulatory activity. Adenosine enhances immunoregulatory activity of Tregs via A2AR signaling. A2AR signaling in effector T cells may induce differentiation into Tregs. There might be a positive feedback loop between adenosine and Treg-dependent immunoregulation. Moreover, adenosine increases tolerogenic APCs, which are poor stimulators of effector T cells. Thus, adenosine suppresses T cell immunity both by directly inhibiting activation of effector T cells and indirectly by producing the immunosuppressive environment. By employing different mechanisms, the immunosuppression by adenosine might be quickly effective and persistent.
Figure 4
Figure 4
Intervention in pathophysiological conditions by modulating the adenosine-A2AR pathway. Enhancement of the adenosine-mediated immunosuppression can be done by directly stimulating A2AR using agonists or by increasing adenosine levels using CD39/73 inducer or inhibitors of nucleoside transporter, adenosine deaminase, and adenosine kinase. This treatment should alleviate various inflammatory disorders. Conversely, weakened adenosine-dependent immunosuppression is expected to enhance anti-pathogen immune response. This modulation will be possible by inhibiting extracellular adenosine production (CD39/73 inhibitor), by enhancing adenosine degradation (adenosine deaminase), or by blocking adenosine binding to A2AR (antagonists).
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