Dopamine inhibits human CD8+ Treg function through D₁-like dopaminergic receptors

CD8+ T regulatory/suppressor cells (Treg)affect peripheral tolerance and may be involved in autoimmune diseases as well as in cancer. In view of our previous data showing the ability of DA to affect adaptive immune responses, we investigated the dopaminergic phenotype of human CD8+ Treg as well as the ability of DA to affect their generation and activity. Results show that CD8+ T cells express both D₁-like and D₂-like dopaminergic receptors (DR), tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of DA, and vesicular monoamine transporter (VMAT)2 and contain high levels of intracellular DA. Preferential upregulation of DR mRNA levels in the CD8+CD28- T cell compartment occurs during generation of CD8+ Treg, which is reduced by DA and by the D₁-like DR agonist SKF-38393. DA and SKF-38393 also reduce the suppressive activity of CD8+ Treg on human peripheral blood mononuclear cells. Treg are crucial for tumor escape from the host immune system, thus the ability of DA to inhibits Treg function supports dopaminergic pathways as a druggable targets to develop original and innovative antitumor strategies.