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New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA 02115
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-
-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.
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 Grants CA112561, CA111985, and AT002788 from the National Institutes of Health (to M.S.).
2 Address correspondence and reprint requests to Dr. Akio Ohta, New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, 113 Mugar Health Sciences Building, Boston, MA 02115. E-mail address: a.ohta{at}neu.edu
3 Abbreviations used in this paper: A2AR, A2A adenosine receptor; A2BR, A2B adenosine receptor; CGS, CGS21680; NECA, 5'-N-ethylcarboxamidoadenosine; PKA, protein kinase A.
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