| Extracellular adenosine is a primordial signal molecule that plays a central role in regulating inflammation and immunity. Primarily generated at sites of hypoxia or physical trauma as the result of the degradation of ATP by the enzymes CD39 and CD73, adenosine is known to be recognized by four G-protein coupled receptors: A1, A2A, A2B, and A3. Of these, the A2A receptor has garnered much interest in the field of immunology due to its high expression on activated immune cells. In this study, we demonstrate that the A2A adenosine receptor plays a critical and non-redundant role in limiting both the initiation—as well as the contraction—of a T cell immune response. Deletion of the A2A adenosine receptor results in a dramatic enhancement in the ability of animals to reject implanted tumor, while also resulting in the generation of robust anti-tumor immunity. Deletion or inhibition of the A2A receptor additionally renders mice more sensitive to immunological anti-tumor therapies. In an effort to determine why the inhibition of A 2A receptor signaling enhances T cell effector function, we observed that A2A receptor suppressed the activity of the evolutionarily conserved serine/threonine kinases mTOR. This effect is mediated by the kinase PKA, and occurs downstream of the mTORC-1 activating protein TSC-2. Furthermore, A2A receptor signaling can inhibit the expression of the intracellular adhesion molecule LFA-1, rendering T cells less able to stably bind with APCs and chemotax across ICAM coated barriers. Lastly, we have demonstrated that while transient inhibition of A2A receptor signaling can enhance the effector phase of a T cell response, A2A receptor signaling is necessary in the resolution phase in girder to facilitate the generation of a pool of quiescent memory cells. These results suggest that modulation of A2A adenosine receptor signaling may allow for an unprecedented level of immunoregulation, presenting potent avenues for either immunosuppression or immune enhancement. |
