Adenosine inhibits activation‐induced T cell expression of CD2 and CD28 co‐stimulatory molecules: Role of interleukin‐2 and cyclic AMP signaling pathways

Abstract

Adenosine is an immunosuppressive molecule that is associated with the microenvironment of solid tumors. Mouse T cells activated with anti-CD3 antibody in the presence of adenosine with or without coformycin (to prevent adenosine breakdown by adenosine deaminase) exhibited decreased tyrosine phosphorylation of some intracellular proteins and were inhibited in their ability to proliferate and synthesize interleukin (IL)-2. In addition, adenosine interfered with activation-induced expression of the co-stimulatory molecules CD2 and CD28. Activation-induced CD2 and CD28 expression was also diminished when T cells were activated in the presence of anti-IL-2 and anti-CD25 antibodies to neutralize IL-2 bioactivity. Collectively, these data suggest that CD2 and CD28 up-regulation following T cell activation is IL-2-dependent; and that adenosine inhibits activation-induced T cell expression of CD2 and CD28 by interfering with IL-2-dependent signaling. The inhibitory effect of adenosine on activation-induced CD2 and CD28 expression could not be attributed to cyclic AMP (cAMP) accumulation resulting from the stimulation of adenylyl cyclase-coupled adenosine receptors, even though cAMP at concentrations much higher than those generated following adenosine stimulation was inhibitory for both CD2 and CD28 expression. We conclude that adenosine interferes with IL-2-dependent T cell expression of co-stimulatory molecules via a mechanism that does not involve the accumulation of intracellular cAMP.

Hypoxia Induces Escape from Innate Immunity in Cancer Cells via Increased Expression of ADAM10: Role of Nitric Oxide

“…It has been reported that hypoxia stimulates in tumor cells the release of immunosuppressive molecules (8)(9)(10), and more recently, that it increases lung cancer cell resistance to cytotoxic T-cell-mediated lysis (11). Other studies have focused on assessing the direct effect of hypoxia on the activity of innate immune effectors rather than on hypoxia-induced adaptations of tumor cells that might endow them with resistance to immunosurveillance (12,13).…”

Expression of A3Adenosine Receptors in Human Lymphocytes: Up-Regulation in T Cell Activation

“…The low potency of the agonist in the stimulation of Ca 2ϩ increase indicates that Cl-IB-MECA elevated calcium by an unknown mechanism that cannot clearly be related to A 3 receptor activation (data not shown). However, there are other effector systems that may be activated by A 3 subtypes to modulate immune functions (Butler et al, 2003), and ongoing studies in our labora- tory are aimed at evaluating the A 3 receptor involvement in cytokine release and its role in the expression of T cells activation markers.…”

The A3Adenosine Receptor: History and Perspectives

“…The nucleoside interferes with activation-induced expression of the costimulatory molecules CD2 and CD28, possibly through A 3 AR recruitment (Butler et al, 2003). However, the adenosine-mediated inhibitory effect on the ability of lymphokine-activated killer cells to kill tumor cells has essentially been attributed to the cAMPelevating A 2A AR (Raskovalova et al, 2005).…”