CD56^brightCD16^- NK cells produce adenosine through a CD38-mediated pathway and act as regulatory cells inhibiting autologous CD4⁺ T cell proliferation

Recent studies suggested that human CD56^brightCD16^- NK cells may play a role in the regulation of the immune response. Since the mechanism(s) involved have not yet been elucidated, in the present study we have investigated the role of nucleotidemetabolizing enzymes that regulate the extracellular balance of nucleotides/nucleosides and produce the immunosuppressive molecule adenosine (ADO). Peripheral blood CD56^dimCD16⁺ and CD56^brightCD16^- NK cells expressed similar levels of CD38. CD39, CD73, and CD157 expression was higher in CD56^brightCD16^- than in CD56^dimCD16⁺ NK cells. CD57 was mostly expressed by CD56^dimCD16⁺ NK cells. CD203a/PC-1 expression was restricted to CD56^brightCD16^- NK cells. CD56^brightCD16^- NK cells produce ADO and inhibit autologous CD4⁺ T cell proliferation. Such inhibition was 1) reverted pretreating CD56^brightCD16^- NK cells with a CD38 inhibitor and 2) increased pretreating CD56^brightCD16^- NK cells with a nucleoside transporter inhibitor, which increase extracellular ADO concentration. CD56^brightCD16^- NK cells isolated from the synovial fluid of juvenile idiopathic arthritis patients failed to inhibit autologous CD4⁺ T cell proliferation. Such functional impairment could be related to 1) the observed reduced CD38/CD73 expression, 2) a peculiar ADO production kinetics, and 3) a different expression of ADO receptors. In contrast, CD56^brightCD16^- NK cells isolated from inflammatory pleural effusions display a potent regulatory activity. In conclusion, CD56^brightCD16^- NK cells act as "regulatory cells" through ADO produced by an ectoenzymes network, with a pivotal role of CD38. This function may be relevant for the modulation of the immune response in physiological and pathological conditions, and it could be impaired during autoimmune/inflammatory diseases.