Abstract
HIV-1 infection is characterized by a chronic activation of the immune system and suppressed function of T lymphocytes. Regulatory CD4+ CD25high FoxP3+CD127low T cells (Treg) play a key role in both conditions. Here, we show that HIV-1 positive patients have a significant increase of Treg-associated expression of CD39/ENTPD1, an ectoenzyme which in concert with CD73 generates adenosine. We show in vitro that the CD39/adenosine axis is involved in Treg suppression in HIV infection. Treg inhibitory effects are relieved by CD39 down modulation and are reproduced by an adenosine-agonist in accordance with a higher expression of the adenosine A2A receptor on patients' T cells. Notably, the expansion of the Treg CD39+ correlates with the level of immune activation and lower CD4+ counts in HIV-1 infected patients. Finally, in a genetic association study performed in three different cohorts, we identified a CD39 gene polymorphism that was associated with down-modulated CD39 expression and a slower progression to AIDS.
Highlights
HIV-1 infection is characterized by chronic immune activation which, in combination with the progressive depletion of CD4+ T cells, profoundly perturbs antigen-specific T cell responses [1]
The population of CD4+CD25high FoxP3+ regulatory T cells (Treg) suppresses antigen-specific T cell responses and controls inappropriate or exaggerated immune activation induced by pathogens, thereby influencing the outcome of various infections [2,3]
Regulatory T cells (Treg) represent a population of lymphocytes that controls inappropriate or exaggerated immune activation induced by pathogens, thereby influencing the outcome of various infections
Summary
HIV-1 infection is characterized by chronic immune activation which, in combination with the progressive depletion of CD4+ T cells, profoundly perturbs antigen-specific T cell responses [1]. The population of CD4+CD25high FoxP3+ regulatory T cells (Treg) suppresses antigen-specific T cell responses and controls inappropriate or exaggerated immune activation induced by pathogens, thereby influencing the outcome of various infections [2,3]. These cells suppress in vitro HIV-1-specific CD4+ and CD8+ effector T-cell responses [2,4]. And functionally distinct subsets of Treg can mediate suppression through distinct mechanisms from secretion of IL-10, TGF-ß, IL-
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