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Front Immunol. 2012 Jul 5;3:190. doi: 10.3389/fimmu.2012.00190. eCollection 2012.

The development and immunosuppressive functions of CD4(+) CD25(+) FoxP3(+) regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway.

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1
New England Inflammation and Tissue Protection Institute, Northeastern University, Boston MA, USA.

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(+) CD25(hi) 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.

KEYWORDS:

A2A adenosine receptor; adenosine; autoimmune; cancer; immunosuppression; regulatory T cells; transplantation

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