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

PLoS Pathogens

Yves Levy¹  Nabila Seddiki²  Jean-Pierre Routy²  Matthieu Carriere²  Jean-Daniel Lelievre²  Elnaz Ghadimi²  Alain Tremblay³  Mohammad-Ali Jenabian⁴  Ayrin Kök⁴  Ahmad Yatim⁴  Jean Sévigny⁴  Mehwish Younas⁴  Anne Hulin⁵ 

[1] Faculty of Dentistry, McGill University, Montréal, Québec, Canada;Faculté de Médecine, Université Paris Est Créteil, Créteil, France;Groupe Henri-Mondor Albert-Chènevière, Laboratory of Pharmacology and Toxicology, Créteil, France;INSERM U955, Equipe 16, Créteil, France;Vaccine Research Institute, Agence Nationale de Recherche sur le Sida et les hépatites virales (ANRS) HIV Vaccine Network (AHVN), Créteil, France

关键词: T cells;    DNA methylation;    HIV infections;    Regulatory T cells;    Adenosine;    Adenylyl cyclase;    Epigenetics;    High performance liquid chromatography;   

DOI  :  10.1371/journal.ppat.1003319

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY