AUTHOR=Ohta Akio , Kini Radhika , Ohta Akiko , Subramanian Meenakshi , Madasu Manasa , Sitkovsky Michail TITLE=The development and immunosuppressive functions of CD4+ CD25+ FoxP3+ regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway JOURNAL=Frontiers in Immunology VOLUME=3 YEAR=2012 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2012.00190 DOI=10.3389/fimmu.2012.00190 ISSN=1664-3224 ABSTRACT=

The A2A adenosine receptor (A2AR)-mediated immunosuppression is firmly implicated in the life-saving down-regulation of collateral tissue damage during the anti-pathogen immune response and in highly undesirable protection of cancerous tissues during anti-tumor immune response. Therefore, depending on specific clinical situation there is a need to either weaken or strengthen the intensity of A2AR signal. While the A2AR-mediated immunosuppression was shown to be T cell autonomous in studies of effector T cells, it was not clear how A2AR stimulation affects regulatory T cells (Treg). Here we show in parallel assays that while A2AR stimulation on T cells directly inhibits their activation, there is also indirect and longer-lasting T cell inhibitory effect through modulation of Treg. A2AR stimulation expanded CD4+ CD25hi FoxP3+ cells, which also express CD39, CD73, and CTLA-4. Treg cultured with A2AR agonist showed increased expression of CTLA-4 and stronger immunosuppressive activity. There was a significant increase of Treg cell number after A2AR stimulation. The CD4+ FoxP3+ population contained those induced from CD4+ CD25− cells, but CD4+ FoxP3+ cells predominantly derived from CD4+ CD25+ natural Treg. Thus, A2AR stimulation numerically and functionally enhanced Treg-mediated immunosuppressive mechanism. These data suggest that the A2AR-mediated stimulation of lymphocytes using A2AR agonists should be considered in protocols for ex vivo expansion of Treg before the transfer to patients in different medical applications.