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.

Critical Role for the Adenosine Pathway in Controlling Simian Immunodeficiency Virus-Related Immune Activation and Inflammation in Gut Mucosal Tissues

“…ϩ Treg expansion strongly correlates with high levels of immune activation and low CD4 ϩ T cell counts (46), while downmodulation of CD39 expression is associated with a slower disease progression in HIV-infected patients (76). On the other hand, CD73…”

“…ϩ Treg expansion is correlated with decreased interleukin-2 (IL-2) production (46). CD4 ϩ CD73 ϩ T cells are depleted in HIV-1-infected patients regardless of viral suppression (47), while peripheral CD73-expressing CD8 ϩ T cells from HIV-infected patients can be partially reversed by antiretroviral therapy (ART) (48).…”

Engineered antigen-specific human regulatory T cells: immunosuppression of FVIII-specific T- and B-cell responses

“…Because Tregs are known to inhibit the production of inflammatory cytokines, 9,11,18,39,40 Figure 2), the CD4 T cells were stained using DR1 tetramers loaded with FVIII-2191-2220 (top contour plots). Expression of Foxp3 and Helios in the gated CD4 1 GFP 1 population were also evaluated by intracellular staining (bottom contour plots).…”

The effect of cellular isolation and cryopreservation on the expression of markers identifying subsets of regulatory T cells

“…For example, expression of CD120b (TNF-α receptor II) identifies a subset with high suppressive function (Mercer et al, 2010,Minigo et al, 2009,Chen et al, 2010). Another subset is defined by expression of CD39, an ecto-nucleoside triphosphate diphosphohydrolase, which facilitates the production of adenosine that inhibits T cell proliferation (Deaglio et al, 2007) and production of IL-2 (Jenabian et al, 2013). T regs have been implicated in the control of immune responses under many physiological and pathological conditions, such as autoimmune diseases, allograft tolerance, tumors, and infectious diseases (Sakaguchi et al, 2010) including, controversially, HIV infection (Imamichi and Lane, 2012).…”