A2A Adenosine Receptor May Allow Expansion of T Cells Lacking Effector Functions in Extracellular Adenosine-Rich Microenvironments

Abstract

Immunosuppressive signaling via the A2A adenosine receptor (A2AR) provokes a mechanism that protects inflamed tissues from excessive damage by immune cells. This mechanism is desirable not only for preventing uncontrolled tissue destruction by overactive immune responses, but also for protecting tumor tissues from antitumor immune responses. In aforementioned circumstances, T cell priming may occur in an environment containing high concentrations of extracellular adenosine. To examine qualitative changes in T cells activated in the presence of adenosine, we asked whether different functional responses of T cells are equally susceptible to A2AR agonists. In this study, we demonstrate that A2AR signaling during T cell activation strongly inhibited development of cytotoxicity and cytokine-producing activity in T cells, whereas the inhibition of T cell proliferation was only marginal. Both CD8+ and CD4+ T cells proliferated well in the presence of A2AR agonists, but their IFN-γ-producing activities were susceptible to inhibition by cAMP-elevating A2AR. Importantly, the impaired effector functions were maintained in T cells even after removal of the A2AR agonist, reflecting T cell memory of the immunoregulatory effect of adenosine. Thus, although the adenosine-rich environment may allow for the expansion of T cells, the functional activation of T cells may be critically impaired. This physiological mechanism could explain the inefficiency of antitumor T cells in the tumor microenvironment.

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“…Adenosine strongly impairs development of effector T cells, especially those that produce IFN-γ and are cytotoxic to tumor cells [84]. Sun et al reported that hypoxia can induce T-cell apoptosis through adenosine/adenosine (2) receptor signaling in vitro [85].…”

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“…Activation of A2A receptors during T-cell activation significantly inhibits cytotoxicity and cytokine production (Ohta et al, 2009) and has been reported to inhibit T-cell proliferation (Zhang et al, 2004;Deaglio et al, 2007). T cells activated in the presence of an A2A receptor agonist maintain a suppressed phenotype after removal of the agonist (Ohta et al, 2009). A2A receptor activation in T cells suppresses the development of both Th1 and Th2 immune responses, in vitro and in vivo (Csoka et al, 2008).…”

“…The A2A receptor dominantly regulates T-cell functions and is significantly upregulated upon T-cell activation. Activation of A2A receptors during T-cell activation significantly inhibits cytotoxicity and cytokine production (Ohta et al, 2009) and has been reported to inhibit T-cell proliferation (Zhang et al, 2004;Deaglio et al, 2007). T cells activated in the presence of an A2A receptor agonist maintain a suppressed phenotype after removal of the agonist (Ohta et al, 2009).…”

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“…The accumulation of extracellular adenosine in tumors generates an immunosuppressive microenvironment that effectively enhances tumor immune escape. Activation of A2A adenosine receptors on T cells has been shown to inhibit T-cell-mediated cytotoxicity, cytokine production (10) and T-cell proliferation (11,12) and to promote T-cell anergy (13).…”