Mohammad-Ali Jenabian 1 , 2 , Nabila Seddiki 1 , 2 , 3 , Ahmad Yatim 1 , 2 , Matthieu Carriere 1 , 2 , Anne Hulin 4 , Mehwish Younas 1 , 2 , Elnaz Ghadimi 5 , Ayrin Kök 1 , 2 , Jean-Pierre Routy 6 , Alain Tremblay 7 , Jean Sévigny 7 , Jean-Daniel Lelievre 1 , 2 , 3 , 8 , Yves Levy 1 , 2 , 3 , 8 , *
25 April 2013
The mechanisms by which Regulatory T cells suppress IL-2 production of effector CD4+ T cells in pathological conditions are unclear. A subpopulation of human Treg expresses the ectoenzyme CD39, which in association with CD73 converts ATP/ADP/AMP to adenosine. We show here that Treg/CD39+ suppress IL-2 expression of activated CD4+ T-cells more efficiently than Treg/CD39−. This inhibition is due to the demethylation of an essential CpG site of the il-2 gene promoter, which was reversed by an anti-CD39 mAb. By recapitulating the events downstream CD39/adenosine receptor (A2AR) axis, we show that A2AR agonist and soluble cAMP inhibit CpG site demethylation of the il-2 gene promoter. A high frequency of Treg/CD39+ is associated with a low clinical outcome in HIV infection. We show here that CD4+ T-cells from HIV-1 infected individuals express high levels of A2AR and intracellular cAMP. Following in vitro stimulation, these cells exhibit a lower degree of demethylation of il-2 gene promoter associated with a lower expression of IL-2, compared to healthy individuals. These results extend previous data on the role of Treg in HIV infection by filling the gap between expansion of Treg/CD39+ in HIV infection and the suppression of CD4+ T-cell function through inhibition of IL-2 production.
Regulatory T cells (Treg) represent a subset of T lymphocytes and have a pivotal role in chronic viral infections and cancer by limiting immune activation. It has been shown that Treg are expanded in chronic HIV infected patients. However, the mechanisms of Treg immune-modulator functions are not clearly known. CD39 is an ectonucleotidase which converts the proinflammatory ATP signal into AMP and the immunosuppressive adenosine in concert with another ecto-enzyme CD73. We have previously reported that CD39/adenosine pathway is involved in AIDS progression. However, the mechanism of Treg immunosuppression through CD39 and its involvement in HIV pathogenesis remains unclear. We report here that Treg/CD39+ inhibits the production of IL-2, a cytokine that stimulates the growth of T lymphocytes, via CD39/Adenosine/cAMP enzymatic pathway. The signals induced by adenosine specific receptor A2AR, increase the intra cellular levels of cAMP. We show that cAMP inhibits CpG site demethylation of the il-2 gene promoter. We found that T cells from HIV patients have a higher expression on A2AR as well as intra-cellular cAMP and a lesser capacity to produce IL-2 upon stimulation than healthy subjects. Our results contribute to elucidate the mechanisms by which Treg suppression occurs during HIV infection.