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

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.

Author Summary

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.

Contributors

Daniel C. Douek: Role: Editor

Journal

Journal ID (nlm-ta): PLoS Pathog

Journal ID (iso-abbrev): PLoS Pathog

Journal ID (publisher-id): plos

Journal ID (pmc): plospath

Title: PLoS Pathogens

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Print): 1553-7366

ISSN (Electronic): 1553-7374

Publication date Collection: April 2013

Publication date (Print): April 2013

Publication date (Electronic): 25 April 2013

Publication date (Corrected, electronic): 29 April 2013

Volume: 9

Issue: 4

Affiliations

[1 ]INSERM U955, Equipe 16, Créteil, France

[2 ]Faculté de Médecine, Université Paris Est Créteil, Créteil, France

[3 ]Vaccine Research Institute, Agence Nationale de Recherche sur le Sida et les hépatites virales (ANRS) HIV Vaccine Network (AHVN), Créteil, France

[4 ]Groupe Henri-Mondor Albert-Chènevière, Laboratory of Pharmacology and Toxicology, Créteil, France

[5 ]Faculty of Dentistry, McGill University, Montréal, Québec, Canada

[6 ]Division of Hematology and Chronic Viral Illness Service, McGill University Health Centre, Montreal, Québec, Canada

[7 ]Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du CHU de Québec, and Département de Microbiologie-Infectiologie et d'Immunologie, Faculté de Médecine, Université Laval, Québec, Québec, Canada

[8 ]Groupe Henri-Mondor Albert-Chènevière, Immunologie Clinique, Créteil, France

National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States of America

Author notes

* E-mail: yves.levy@ 123456hmn.aphp.fr

The authors have declared that no competing interests exist.

Conceived and designed the experiments: MAJ NS YL. Performed the experiments: MAJ AY MY MC AH AK AT. Analyzed the data: MAJ NS JDL YL EG JPR JS. Contributed reagents/materials/analysis tools: JDL JPR JS. Wrote the paper: MAJ NS YL.

Article

Publisher ID: PPATHOGENS-D-12-02067

DOI: 10.1371/journal.ppat.1003319

PMC ID: 3635970

PubMed ID: 23658513

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Page count

Pages: 11

Funding

This work was supported by ANRS (Agence Nationale de Recherche contre le SIDA et les hépatites virales). JS receives supports from Canadian Institutes of Health Research (CIHR) and FRQ-S. JPR receives supports from AIDS and Infectious Diseases Network of FRQ-S, Canadian HIV trial network and CIHR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Categories

Subject: Research Article

Subject: Biology

Subject: Immunology

Subject: Immune Cells

Subject: T Cells

Subject: Immunity

Subject: Immune Activation

Subject: Immunity to Infections

Subject: Immunopathology

Subject: Medicine

Subject: Infectious Diseases

Subject: Viral Diseases

Subject: HIV

Subject: Retrovirology and HIV immunopathogenesis