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.
Highlights
It is no longer controversial and it is widely accepted that there are professionally immunosuppressive regulatory T cells (Treg), which have been first identified and characterized by observations of autoimmunity in mice depleted of CD4+ CD25+ T cell subpopulation (Sakaguchi et al, 1982, 1985)
It is believed that the adenosineA2AR pathway has evolved as a negative feed-back immunosuppressive mechanism that limits the extent of the collateral tissue damage by activated immune cells during anti-pathogen responses (Sitkovsky and Lukashev, 2005; Sitkovsky and Ohta, 2005)
We have shown that stimulation of A2A adenosine receptor (A2AR) inhibits activation of effector T cells and their effector functions (Ohta et al, 2009)
Summary
It is no longer controversial and it is widely accepted that there are professionally immunosuppressive regulatory T cells (Treg), which have been first identified and characterized by observations of autoimmunity in mice depleted of CD4+ CD25+ T cell subpopulation (Sakaguchi et al, 1982, 1985). It is believed that the adenosineA2AR pathway has evolved as a negative feed-back immunosuppressive mechanism that limits the extent of the collateral tissue damage by activated immune cells during anti-pathogen responses (Sitkovsky and Lukashev, 2005; Sitkovsky and Ohta, 2005). This mechanism may regulate the other major, but evolutionary younger immunosuppressive mechanisms including Treg (Pouliot et al, 2002; Cadieux et al, 2005; Sitkovsky, 2009)
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