A2A adenosine receptor may allow expansion of T cells lacking effector functions in extracellular adenosine-rich microenvironments.
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-gamma-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.
New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, 113 Mugar Health Sciences Building, Boston, MA 02115, USA. a.ohta@neu.edu
Akio
A
Ohta
Akiko
A
Ohta
Manasa
M
Madasu
Radhika
R
Kini
Meenakshi
M
Subramanian
Nipun
N
Goel
Michail
M
Sitkovsky
D000241:Adenosine / Q000378:metabolism* / Q000502:physiology; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D005110:Extracellular Space / Q000276:immunology* / Q000378:metabolism*; D006131:Growth Inhibitors / Q000819:agonists / Q000502:physiology; D007108:Immune Tolerance; D018836:Inflammation Mediators / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D043705:Receptor, Adenosine A2A / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
D058908:Adenosine A2 Receptor Agonists; D016207:Cytokines; D006131:Growth Inhibitors; D018836:Inflammation Mediators; D043705:Receptor, Adenosine A2A; D000241:Adenosine