Abstract
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.
Highlights
Regulatory T cells (Treg) play a dominant role in self-tolerance, control of autoimmune diseases and control of chronic infections by suppressing effector T cells activation, proliferation and functions [1]
These results show that Treg/CD39+ inhibit, at least partially, the expression of IL-2 through the enzymatic activity of CD39
The results demonstrate the catalysis of exogenous ATP into adenosine diphosphate (ADP) and adenosine monophosphate (AMP) in the presence of purified Treg/CD39+ but not Treg/CD392
Summary
Regulatory T cells (Treg) play a dominant role in self-tolerance, control of autoimmune diseases and control of chronic infections by suppressing effector T cells activation, proliferation and functions [1]. Induced Treg are heterogeneous and their phenotype and frequency vary across different disease states. They include interleukin-10 (IL-10) producing Tr1, transforming growth factor (TGF-b-expressing Th3 cells) [6,7] and Foxp3+CD39+ effector/memory Tregs [8]. Treg can suppress anti-HIV specific CD4+ and CD8 T cell responses by inhibiting cytokine production and cell proliferation [13,14]. Increased Treg frequency at the mucosal site is accompanied by increased immune activation and decreased HIV-specific T-cell responses [15]. In HIV controllers, low frequencies of Treg have been associated with effective adaptive immune responses, and with generalized immune activation and CD4 depletion [18]
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