Regulatory T Cells Negatively Affect IL-2 Production of Effector T Cells through CD39/Adenosine Pathway in HIV Infection

• Published in: PLoS pathogens Vol. 9; no. 4; p. e1003319
• Main Authors: Jenabian, Mohammad-Ali, Seddiki, Nabila, Yatim, Ahmad, Carriere, Matthieu, Hulin, Anne, Younas, Mehwish, Ghadimi, Elnaz, Kök, Ayrin, Routy, Jean-Pierre, Tremblay, Alain, Sévigny, Jean, Lelievre, Jean-Daniel, Levy, Yves
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.04.2013; Public Library of Science (PLoS)
• Subjects: 5'-Nucleotidase - metabolism; Adenosine; Adenosine - metabolism; Antibodies, Monoclonal - immunology; Antigens, CD - biosynthesis; Antigens, CD - immunology; Antigens, CD - metabolism; Apyrase - biosynthesis; Apyrase - immunology; Apyrase - metabolism; Biology; Cell Proliferation; Cyclic AMP - metabolism; DNA Methylation; Health aspects; HIV; HIV infection; HIV Infections - immunology; HIV-1 - immunology; Host-parasite relationships; Human immunodeficiency virus; Humans; Immune system; Interleukin-2; Interleukin-2 - biosynthesis; Interleukin-2 - genetics; Lymphocyte Activation; Medical research; Medicine; Physiological aspects; Promoter Regions, Genetic; Proteins; Receptor, Adenosine A2A - metabolism; T cell receptors; T cells; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; France; Canada
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1003319

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.